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Inflammatory caspases, including caspase-11, are upregulated in CD8+ T cells after Ag-specific activation, but little is known about their function in T cells. We report that caspase-11–deficient (Casp11−/−) T cells proliferated more readily in response to low-affinity and low-abundance ligands both in vitro and in vivo due to an increased ability to signal through the TCR. In addition to increased numbers, Casp11−/− T cells had enhanced effector function compared with wild-type cells, including increased production of IL-2 and reduced expression of CD62L. Casp11−/− T cells specific for endogenous Ags were more readily deleted than wild-type cells. These data indicate that caspase-11 negatively regulates TCR signaling, possibly through its ability to regulate actin polymerization, and inhibiting its activity could enhance the expansion and function of low-affinity T cells.

The study of T cell immunity at barrier surfaces has largely focused on T cells bearing the αβ TCR. However, T cells that express the γδ TCR are disproportionately represented in peripheral tissues of mice and humans, suggesting they too may play an important role responding to external stimuli. In this article, we report that, in a murine model of cutaneous infection with vaccinia virus, dermal γδ T cell numbers increased 10-fold in the infected ear and resulted in a novel γδ T cell population not found in naive skin. Circulating γδ T cells were specifically recruited to the site of inflammation and differentially contributed to dermal populations based on their CD27 expression. Recruited γδ T cells, the majority of which were CD27+, were granzyme B+ and made up about half of the dermal population at the peak of the response. In contrast, recruited and resident γδ T cell populations that made IL-17 were CD27−. Using a double-chimera model that can discriminate between the resident dermal and recruited γδ T cell populations, we demonstrated their divergent functions and contributions to early stages of tissue inflammation. Specifically, the loss of the perinatal thymus-derived resident dermal population resulted in decreased cellularity and collateral damage in the tissue during viral infection. These findings have important implications for our understanding of immune coordination at barrier surfaces and the contribution of innate-like lymphocytes on the front lines of immune defense.

We used a newly generated T-cell receptor mimic monoclonal antibody (TCRm MAb) that recognizes a known nonself immunodominant peptide epitope from West Nile virus (WNV) NS4B protein to investigate epitope presentation after virus infection in C57BL/6 mice. Previous studies suggested that peptides of different length, either SSVWNATTAI (10-mer) or SSVWNATTA (9-mer) in complex with class I MHC antigen H-2Db, were immunodominant after WNV infection. Our data establish that both peptides are presented on the cell surface after WNV infection and that CD8+ T cells can detect 10- and 9-mer length variants similarly. This result varies from the idea that a given T-cell receptor (TCR) prefers a single peptide length bound to its cognate class I MHC. In separate WNV infection studies with the TCRm MAb, we show that in vivo the 10-mer was presented on the surface of uninfected and infected CD8α+CD11c+ dendritic cells, which suggests the use of direct and cross-presentation pathways. In contrast, CD11b+CD11c− cells bound the TCRm MAb only when they were infected. Our study demonstrates that TCR recognition of peptides is not limited to certain peptide lengths and that TCRm MAbs can be used to dissect the cell-type specific mechanisms of antigen presentation in vivo.

Folliculin-interacting protein 1 (Fnip1) is an adaptor protein that physically interacts with AMPK, an energy-sensing kinase that stimulates mitochondrial biogenesis and autophagy in response to low ATP, while turning off energy consumption mediated by mammalian target of rapamycin. Previous studies with Fnip1-null mice revealed that Fnip1 is essential for pre-B-cell development. Here we report a critical role of Fnip1 in invariant natural killer T (iNKT) cell development. Thymic iNKT development in Fnip1(-/-) mice was arrested at stage 2 (NK1.1(-)CD44(+)) but development of CD4, CD8, γδ T-cell, and NK cell lineages proceeded normally. Enforced expression of a Vα14Jα18 iNKT TCR transgene or loss of the proapoptotic protein Bim did not rescue iNKT cell maturation in Fnip1(-/-) mice. Whereas most known essential transcription factors for iNKT cell development were represented normally, Fnip1(-/-) iNKT cells failed to down-regulate Promyelocytic leukemia zinc finger compared with their WT counterparts. Moreover, Fnip1(-/-) iNKT cells contained hyperactive mTOR and reduced mitochondrial number despite lower ATP levels, resulting in increased sensitivity to apoptosis. These results indicate that Fnip1 is vital for iNKT cell development by maintaining metabolic homeostasis in response to metabolic stress.

SummaryTissue-resident memory T (Trm) cells represent a population of memory CD8+ T cells that can act as first responders to local infection. The mechanisms regulating the formation and maintenance of intestinal Trm cells remain elusive. Here we showed that transforming growth factor-β (TGF-β) controlled both stages of gut Trm cell differentiation through different mechanisms. During the formation phase of Trm cells, TGF-β signaling inhibited the migration of effector CD8+ T cells from the spleen to the gut by dampening the expression of integrin α4β7. During the maintenance phase, TGF-β was required for the retention of intestinal Trm cells at least in part through the induction of integrins αEβ7 and α1, as well as CD69. Thus, the cytokine acts to control cytotoxic T cell differentiation in lymphoid and peripheral organs.

CD4 and CD8 T lymphocytes are adaptive immune cells that play a key role in the immune response to pathogens. They have been extensively studied in a variety of model systems and the mechanisms by which they function are well described. However, the responses by these cell types vary widely from pathogen to pathogen. In this review, we will discuss the role of CD8 and CD4 T cells in the immune response to West Nile virus infection.

During an infection the antigen non-specific memory CD8 T cell compartment is not simply an inert pool of cells, but becomes activated and cytotoxic. It is unknown how these cells contribute to the clearance of an infection. We measured the strength of T-cell receptor (TCR) signals that bystander activated, cytotoxic CD8 T-cells (BA-CTLs) receive in vivo and found evidence of limited TCR signaling. Given this marginal contribution of the TCR, we asked how BA-CTLs identify infected target cells. We show that target cells express NKG2D ligands following bacterial infection and demonstrate that BA-CTLs directly eliminate these target cells in an innate-like, NKG2D-dependent manner. Selective inhibition of BA-CTL mediated killing led to a significant defect in pathogen clearance. Together these data suggest a previously unappreciated, innate role for memory CD8 T-cells in the early immune response before the onset of a de-novo generated, antigen-specific CD8 T-cell response.

Tissue resident memory (Trm) CD8 T cells represent a newly described memory T cell population. We have previously characterized a population of Trm cells that persists within the brain after acute virus infection. Although capable of providing marked protection against a subsequent local challenge, brain Trm cells do not undergo recall expansion after dissociation from the tissue. Furthermore, these Trm cells do not depend on the same survival factors as the circulating memory T cell pool as assessed either in vivo or in vitro. To gain greater insight into this population of cells, we compared the gene expression profiles of Trm cells isolated from the brain with those of circulating memory T cells isolated from the spleen after an acute virus infection. Trm cells displayed altered expression of genes involved in chemotaxis, expressed a distinct set of transcription factors, and overexpressed several inhibitory receptors. Cumulatively, these data indicate that Trm cells are a distinct memory T cell population disconnected from the circulating memory T cell pool and display a unique molecular signature that likely results in optimal survival and function within their local environment.

T cell-specific deletion of the receptor for transforming growth factor-β (TGF-β) mediated by Cre recombinase expressed early in T cell development leads to early-onset lethal autoimmune disease that cannot be controlled by regulatory T cells. However, when we deleted that receptor through the use of Cre driven by a promoter that is active much later in T cell development, adult mice in which most peripheral CD4(+) or CD8(+) T cells lacked the receptor for TGF-β showed no signs of autoimmunity. Because of their enhanced responses to weak stimulation of the T cell antigen receptor, when transferred into lymphopenic recipients, naive TGF-β-unresponsive T cells underwent much more proliferation and differentiation into effector cells and induced lymphoproliferative disease. We propose that TGF-β signaling controls the self-reactivity of peripheral T cells but that in the absence of TGF-β signals, an added trigger such as lymphopenia is needed to drive overt autoimmune disease.

The molecular mechanisms that regulate mature T cell fate and enable cells to differentiate into memory T cells are largely unknown. Memory T cells share certain key features with stem cells: they both have the ability to self-renew and are long-lived. The Wnt–β-catenin signaling pathway is a key player in regulating stem cell self-renewal and differentiation. We generated a conditional knockout mouse that specifically lacks β-catenin in mature T cells and report in this article that β-catenin is not involved in regulating effector versus memory T cell differentiation. β-catenin–deficient memory T cells were phenotypically and functionally indistinguishable from control cells and made normal recall responses. β-catenin deficiency does not affect T cell migration, T cell function in a model of chronic infection, or lymphopenia-induced proliferation. Together, our data suggest that self-renewal and differentiation are regulated differently in memory T cells compared with epithelial and hematopoietic stem cells.

After an infection, cytotoxic T lymphocyte precursors proliferate and become effector cells by recognizing foreign peptides in the groove of major histocompatibility complex (MHC) class I molecules expressed by antigen-presenting cells (APCs). Professional APCs specialized for T-cell activation acquire viral antigen either by becoming infected themselves (direct presentation) or by phagocytosis of infected cells, followed by transfer of antigen to the cytosol, processing and MHC class I loading in a process referred to as cross-presentation. An alternative way, referred to as 'cross-dressing', by which an uninfected APC could present antigen was postulated to be by the transfer of preformed peptide-MHC complexes from the surface of an infected cell to the APC without the need of further processing. Here we show that this mechanism exists and boosts the antiviral response of mouse memory CD8(+) T cells. A number of publications have demonstrated sharing of peptide-loaded MHC molecules in vitro. Our in vitro experiments demonstrate that cross-dressing APCs do not acquire peptide-MHC complexes in the form of exosomes released by donor cells. Rather, the APCs and donor cells have to contact each other for the transfer to occur. After a viral infection, we could isolate cross-dressed APCs able to present viral antigen in vitro. Furthermore, using the diphtheria toxin system to selectively eliminate APCs that could only acquire viral peptide-MHC complexes by cross-dressing, we show that such presentation can promote the expansion of resting memory T cells. Notably, naive T cells were excluded from taking part in the response. Cross-dressing is a mechanism of antigen presentation used by dendritic cells that may have a significant role in activating previously primed CD8(+) T cells.

Mycobacterium tuberculosis (Mtb) frequently establishes persistent infections that may be facilitated by mechanisms that dampen immunity. T regulatory (T reg) cells, a subset of CD4(+) T cells that are essential for preventing autoimmunity, can also suppress antimicrobial immune responses. We use Foxp3-GFP mice to track the activity of T reg cells after aerosol infection with Mtb. We report that during tuberculosis, T reg cells proliferate in the pulmonary lymph nodes (pLNs), change their cell surface phenotype, and accumulate in the pLNs and lung at a rate parallel to the accumulation of effector T cells. In the Mtb-infected lung, T reg cells accumulate in high numbers in all sites where CD4(+) T cells are found, including perivascular/peribronchiolar regions and within lymphoid aggregates of granulomas. To determine the role of T reg cells in the immune response to tuberculosis, we generated mixed bone marrow chimeric mice in which all cells capable of expressing Foxp3 expressed Thy1.1. When T reg cells were depleted by administration of anti-Thy1.1 before aerosol infection with Mtb, we observed approximately 1 log less of colony-forming units of Mtb in the lungs. Thus, after aerosol infection, T reg cells proliferate and accumulate at sites of infection, and have the capacity to suppress immune responses that contribute to the control of Mtb.

Technological advances in recent years have allowed for an ever-expanding ability to analyze and quantify in vivo immune responses. MHC tetramers, intracellular cytokine staining, an increasing repertoire of transgenic and “knockout” mice, and the detailed characterization of a variety of infectious models have all facilitated more precise and definitive analyses of the generation and function of cytotoxic T lymphocytes (CTL). Understanding the mechanisms behind the differentiation of effector and memory CTL is of increasing importance to develop vaccination strategies against a variety of established and emerging infectious diseases. This review focuses on recent advances in our understanding of how effector and memory CTL differentiate and survive in vivo in response to viral or bacterial infection.

An aquifer test involving seven days of pumping and five days of recovery was performed in the unconfined aquifer at Canadian Forces Base Borden in Ontario, Canada. Hydraulic head levels were intensively monitored in eleven observation wells, and moisture content profiles were frequently logged using a neutron moisture probe at six different radial distances from the pumping well. Capillary fringe thickness variations were inferred by comparing these hydraulic and moisture content measurements. Allowing for the effects of lithologic variations, the response of the moisture content profile is predominately characterized by a downward translation during pumping-induced drainage. Our observations indicate that there is minimal excess storage above the capillary fringe at late times. The capillary fringe extended significantly with pumping in comparison to its static thickness; this extension progressively increased during the entire test. The capillary fringe extension decreased with increasing radial distance and was inferred to have eventually extended out to between 20 and 25 m. This extension represented a significant volume of excess capillary fringe storage that persisted into late times. A direct relationship between the vertical gradients below the water table and the excess capillary fringe storage is not apparent from these experimental data. Analogous to the pumping test observations, the response of the moisture content profile during recovery is essentially an upward translation. While the hydraulic head levels recovered nearly to their pre-pumping elevations, the moisture content profiles stabilized approximately 0.20 m below their pre-pumping positions. This recovery differential leads to a capillary fringe compression that converted excess storage during pumping into storage deficit during recovery. In contrast to the significant radial variation of the capillary fringe extension during pumping, the capillary fringe compression is relatively uniform out to at least 15 m during the late recovery stage. The recovery deficit and entrapped residual air observed below the upward translating transition zone are strong indications that significant hysteretic processes are occurring at the field scale.

Ground penetrating radar (GPR) profiling is a non-invasive geophysical technique that has been used by Endres et al. [Ground Water 38 (2000) 566] to successfully image pumping-induced drainage in an unconfined aquifer. However, the drained water volume calculated from the GPR data was significantly less than the actual pumped volume. To investigate the reasons for this discrepancy, a seven-day pumping test and five-day recovery test was performed at Canadian Forces Base Borden in Ontario, Canada. A dense spatial coverage of GPR profiles was used to better quantify variations in drainage due to small-scale aquifer heterogeneity. In addition, a neutron moisture content probe was used to directly observe drainage and the soil moisture profile at a sealed well near the pumping well. Neutron logging indicated that the transition zone translated downward during pumping without undergoing significant extension. Comparison of the GPR- and neutron-derived transition zone drawdowns show nearly equal responses. Both of these observations support the hypothesis that the behaviour of the GPR reflection is an accurate measure of the transition zone response. In contrast, transition zone drawdown obtained from both GPR and neutron logging are significantly delayed relative to potentiometric drawdown, resulting in an extended capillary fringe. The drained water volume was determined from the GPR-derived transition zone drawdown data using a number of different approaches. Methods that incorporated information about spatial variations in drainage gave larger estimates of drained water volume; however, those estimates were still lower than the actual pumped volume. The unaccountable volume of water could be a result of several factors—aquifer heterogeneity may still not be adequately represented by the increased GPR coverage, and/or leakage from the underlying aquitard may be providing a significant volume of water.

The CD8+cytotoxic T cell response to pathogens is thought to be CD4+helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+T cells mount a primary CD8 response toListeria monocytogenesequal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+T cells from normal mice can respond rapidly, but memory CD8+T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development.

Tolerance to self is engendered by multiple mechanisms. Lymph node stromal cells are now found to contribute to self-tolerance by their endogenous expression of peripheral tissue antigens.

P14 mice expressing a transgenic TCR specific for the lymphocytic choriomeningitis virus glycoprotein p33 epitope were used to study the induction of CTL effector activity by a variety of ligands. Surprisingly, p33 variants which are weaker agonists for the P14 TCR than the wild-type p33 peptide were able to induce more potent effectors with a broader range of cytolytic specificity. Similarly, low concentrations of p33 were more effective than higher concentrations. These results correlated with no or only moderate TCR down-regulation by variants of p33 and low p33 concentrations. This phenotype observed after 18 h of culture was transient as progressive restoration of reactivity was observed at 42 or 66 h in the cultures stimulated with high p33 concentrations and this correlated with recovery of TCR surface levels. TCR down-regulation was blocked by src family kinase inhibitors. These findings indicate that the specificity of a T cell can be fine-tuned by the nature of the primary stimulus correlating with surface TCR level and imply an important role for src family kinases in the differential regulation of surface TCR levels upon TCR engagement by different ligand/MHC complexes.

Cytotoxic T cells (CTL) play a critical role in the murine immune response to Listeria monocytogenes (Listeria). Bacterial antigens are presented to Listeria-specific CTL by products of both conventional, polymorphic MHC class Ia and non-polymorphic MHC class Ib alleles. The H2-M3 class Ib gene product, M3, preferentially presents formylmethionine-initiating (fMet) peptides derived from the N termini of bacterial and mitochondrial proteins. Thus, M3 signals the presence of bacterial invaders to CTL effectors. Listeria-encoded fMet peptide epitopes for H2-M3-restricted CTL have recently been identified. These and other identified fMet peptides are predominantly comprised of hydrophobic residues and appear to be cleaved from membrane-bound proteins. The subcellular location and membrane topology of such proteins may be significant factors in their selection as target antigens for H2-M3-restricted CTL. Such rules may prove useful for prediction of candidate fMet peptide epitopes from other bacterial proteins and species. Studies using synthetic fMet peptides to stimulate CTL ex vivo are also discussed. These latter studies indicate that Listeria infection boosts H2-M3-restricted CTL responses. However, in contrast to MHC class Ia-restricted CTL responses, fMet peptide-specific CTL are observed in a large proportion of cultures from non-immunized, conventionally housed (non-SPF) mice. The CTL activity in these latter cultures may reflect priming in vivo on cross-reactive antigens, or may indicate that requirements for priming of H2-M3-restricted CTL are less stringent than for class Ia-restricted responses.

Contrary to results of previous studies using high frequencies of T cell receptor–transgenic T cells, new data indicate that when naive precursor frequencies approach endogenous levels, CD8+ effector and central memory T cell lineage commitment is fixed.

In the lymphoid system, T cells respond to space or under-crowding by dividing to maintain their numbers. In this issue of Cell, evidence is provided that this homeostatic proliferation, coupled with excess production of a cytokine, IL-21, is a key factor in susceptibility to autoimmune diabetes.

Over the last two decades the molecular and cellular mechanisms underlying T cell activation, expansion, differentiation, and memory formation have been intensively investigated. These studies revealed that the generation of memory T cells is critically impacted by a number of factors, including the magnitude of the inflammatory response and cytokine production, the type of dendritic cell [DC] that presents the pathogen derived antigen, their maturation status, and the concomitant provision of costimulation. Nevertheless, the primary stimulus leading to T cell activation is generated through the T cell receptor [TCR] following its engagement with a peptide MHC ligand [pMHC]. The purpose of this review is to highlight classical and recent findings on how antigen recognition, the degree of TCR stimulation, and intracellular signal transduction pathways impact the formation of effector and memory T cells.

We describe a novel method for screening large libraries of random peptides for T cell antigens. Two libraries were constructed, containing fixed amino acids representing the major histocompatibility complex (MHC) class I anchor residues for H-2Kb-restricted octamers and H-2Db-restricted nonamers. Peptides from the Kb-restricted library (KbL: SXIXFXXL) and the Db-restricted library (DbL: XXXXNXXXIM) specifically stabilize empty Kb and Db molecules, respectively. The libraries contain peptides that mimic several H-2b-restricted cytotoxic T lymphocyte epitopes, and 21 mimotopes for a Db-restricted H-Y epitope were isolated. A degenerate synthetic peptide of limited complexity containing the identified H-Y sequence motif was found to be similar to the natural H-Y epitope by reverse-phase high performance liquid chromatography analysis. This peptide is also capable of immunizing female mice against male splenocytes. Several applications for MHC-restricted peptide libraries are discussed.

Naive lymphocytes have a finite lifespan and are continually replaced by input from generative organs. In contrast, memory cells or their progeny can last a lifetime. The expanded populations of memory cells and their more widespread distribution provide protection against recurrent infection.

There is debate over whether effective T-cell mediated protection against a second infection, or post-vaccination, is better done by central memory cells or effector memory cells. The former may have greater powers of expansion, whereas the latter may be closer to the site of pathogen entry and faster to respond. This review focuses on memory T cells which are not recirculating but which remain at the peripheral site of initial pathogen or vaccine encounter, so-called tissue-resident memory cells. They may play key roles in protection against re-eruption of latent viral infections and at mucosal surfaces.

The T cell receptor (TcR) on CD8+ T lymphocytes recognizes a complex which consists of a major histocompatibility complex (MHC) heavy chain, beta 2-microglobulin (beta 2M), and peptide on the surface of antigen-presenting cells. Mutational analyses have suggested that the TcR recognizes both the alpha 1 and alpha 2 domains of the heavy chain as well as the peptide. In light of this, it is of interest to know to what extent the heavy chain domains take on distinct conformations when bound to individual peptides. It has recently been shown that antibodies which recognize the Kb MHC complex are sensitive to which peptides are bound in the groove. We have extended this analysis to include eight Kb-specific antibodies, seven of which are peptide sensitive. These antibodies, all of which are allo-antibodies, recognize Kb-bearing cells which, it is now appreciated, have a highly heterogeneous mix of self peptides presented in their grooves. We show that these self peptides also can affect antibody binding. It has been suggested that peptides alter the conformation of the alpha 1 and alpha 2 domains of the heavy chain and that this in turn affects the recognition of Kb by antibody. An alternative hypothesis is that solvent-exposed peptide side chains may prevent the antibody from binding the complex. Using a panel of 128 single-amino acid variants of a Kb-binding antigenic peptide from ovalbumin we show that for most Kb-specific antibodies, the second idea is more likely. Those variants which prevent antibody binding are at solvent exposed positions, and in general, the bulkier the side chain, the greater the inhibition of antibody binding. However, in the case of two antibodies, 100.30 and 34.4.20, the peptide residues which affect antibody recognition are buried, suggesting that these antibodies see an alternate conformation of the peptide/MHC complex.

An important attribute of the adaptive immune system is the ability to remember a prior encounter with a pathogen; an ability termed immunological memory. Bigger, better, and stronger responses are mounted upon a secondary encounter with the pathogen potentially resulting in clearance of the infection before the development of disease. We will review recent advances in the field of memory CD8(+) T cell differentiation focusing on both intrinsic and extrinsic factors that govern the development of T cell memory.

CD4 single positive thymocytes are the fraction of mature thymocytes that contains precursors of MHC class II restricted T cells. In the experiments presented here, we demonstrate phenotypic and functional heterogeneity amongst CD4 single positive thymocytes from adult mice. Approximately 70% of these cells adhere to anti-CD8 antibody-coated dishes and therefore express low levels of CD8 molecules. They are referred to here as CD8loCD4hi. The remaining 30% are CD8-CD4hi. The CD8loCD4hi subset also expresses 3-fold higher surface levels of heat-stable antigen (HSA) than CD8-CD4hi thymocytes. Both CD4hi subsets express high levels of the alpha beta TCR/CD3 complex on the cell surface, and can proliferate in response to allogeneic cells expressing MHC class II differences but not to cells expressing only class I disparate molecules. However, CD8-CD4hi thymocytes are self-sufficient in such a proliferative response, whereas CD8loCD4hi thymocytes require exogenous IL-2 for optimal proliferation. The results suggest that CD8loCD4hi thymocytes are not completely mature. Their phenotype suggests that they might be descendants from CD8hiCD4hi double positive thymocytes, and that they have begun to down-regulate gradually CD8 and HSA molecules. The relationship between the two CD4hi single positive subsets is discussed.

Cytotoxic T lymphocytes (CTLs) that express the CD8 co-receptor are the guided missiles of the immune system. They express clonally distributed receptors for foreign antigen, undergo marked proliferation in response to infection and kill any cell that expresses their target antigen. When an infection is cleared or brought under control, the progeny of these cytolytic effectors are retained as an essential component of immunological memory. As I discuss here, similar to other aspects of immunity, their clonal expansion and survival depend on the activity of CD4+ T cells, although the mechanism(s) of 'help' for CTL responses is still debated.

In the lymphoid system, T cells respond to space or under-crowding by dividing to maintain their numbers. In this issue of Cell, evidence is provided that this homeostatic proliferation, coupled with excess production of a cytokine, IL-21, is a key factor in susceptibility to autoimmune diabetes.

Two therapeutic drugs have been found to enhance memory in immune cells called T cells, apparently by altering cellular metabolism. Are changes in T-cell metabolism the key to generating long-lived immune memory?

The selection of T cells requires their exposure to a repertoire of peptides generated by an organelle whose structure is thymus-specific.

The immune effect of a cytokine bound to an antibody is paradoxically much stronger than that of the cytokine alone, suggesting a way to lower therapeutic doses and thereby reduce side effects.

During persistent infections, the immune cells responsible for killing infected cells and maintaining inflammation gradually stop functioning, allowing the pathogen to thrive. But can this process be reversed? It's common in chronic viral disease for the immune system to grow accustomed to the infection. Normally CD8 T cells retain a ‘memory’ of the viruses they encounter, so they can respond rapidly to a new infection. In a chronic infection the memory cells lose this capacity, but the nature of this ‘exhausted’ state is not well understood. Barber et al. have now found a possible cause in a study of a mouse infection model. The inhibitory immune receptor gene PD-1 is much more active in exhausted than in normal CD8 T cells, and administration of antibodies that block PD-1 action restores function in virus-specific T cells and also reduces virus levels. The discovery of a T-cell exhaustion mechanism suggests a route to immunological strategies for treating chronic viral infections.

Memory T cells help us to fight off infectious microorganisms that we have encountered before. There are two models for the generation of memory cells, and new work provides support for one of them.

The newly rearranged T cell receptor on the surface of immature thymocytes must interact with not too much and not too little affinity for self-peptide–MHC ligands to allow the cell to mature and emigrate to the lymphoid periphery. Recent experiments shed new light on how the signal is perceived as “just right”.

Cytotoxic T lymphocytes (CTLs) recognize class I major histocompatibility complex (MHC) molecules associated with antigenic peptides derived from endogenously synthesized proteins. Binding to such peptides is a requirement for class I assembly in the endoplasmic reticulum (ER). A mutant human cell line, T2, assembles and transports to its surface some, but not all, class I MHC molecules. The class I molecules expressed on the surface of T2 do not present peptides derived from cytosolic antigens, although they can present exogenously added peptides to CTL. The transported class I molecules may interact weakly with an unknown retaining factor in the ER such that they can assemble despite the relative shortage of peptides.

A technology is described which combines the power of T lymphocytes in eliminating unwanted cells and causing beneficial inflammatory reactions with the great advantages of monoclonal antibodies. We show that heteroconjugate antibodies and hybrid antibodies, in which one of the component binding sites is anti-T-cell receptor and the other component binding is directed against any chosen target antigen, can focus T cells to act at the targeted site. We present experimental evidence for the in vitro efficacy of this system in viral infections and in the elimination of tumor cells. In an in vivo tumor model pilot experiments have been undertaken that resulted in a significant higher rate of survival of animals treated with hybrid antibodies compared to untreated animals.

The murine monoclonal antibody F23.1 reacts with an allotypic determinant on the T cell receptors of about 25% of peripheral T lymphocytes in most common mouse strains. In this report we demonstrate that this IgG2a antibody bound to the receptor of a cytotoxic effector T cell can direct that cell to lyse any target cell which expresses receptors for IgG2a. Thus, allotype-positive, Lyt-2+ T lymphocytes from either concanavalin A- or F23.1-activated cell cultures are recruited as cytotoxic effector cells which lyse targets via the Fc receptor. Concanavalin A-induced T cell blasts depleted of Lyt-2+ cells do not mediate cytotoxic effects in this system. The data presented here confirm earlier observations that monoclonal anti-T cell receptor antibodies attached to the surface of a cell can act as target structures for T cell-mediated lysis.

The murine monoclonal antibody F23.1 reacts with an allotypic determinant on the beta chain of the T cell receptor expressed by approximately 20% of T helper and cytotoxic T lymphocytes of most common mouse strains. This IgG2a antibody, either in soluble form or covalently coupled to Sepharose beads, can activate resting T cells from naive animals to proliferate. Interestingly, under all conditions of activation, the antibody can only induce proliferation if exogenous lymphokines in the form of Con A supernatant are provided. Thus, it is unlike most lectins and anti-T3 antibodies in this regard. Furthermore, under all conditions of culture, F23.1 activates preferentially the Lyt-2+ subset of T cells. This is the case even in the presence of accessory cells. Further evidence is provided that two soluble lymphokines, different from IL2, are required to initiate IL2-dependent growth and to allow the expression of lytic activity.