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The article investigates the long-term impact of interleukin (IL)-2 therapy on HIV infection by researchers from Milan, Italy. In this study, the researchers focused on immunologic and virologic consequences and long-term impact of intermittent IL-2 therapy on HIV-infected patients. In conclusion, the correlates of IL-2-induced immunoogic reconstitution, in addition to the restoration of a normal number of circulating CD4 T-cells, remain to be fully uncovered.

This article discusses the role of regulatory T cells in treating autoimmune diseases. In the early 1970s, the concept of specialized regulatory cells in the immune system was suggested for the first time. According to the authors, alopecia areata is a suspected autoimmune disease in which the hair follicles are targeted by CD4+ and CD8+ lymphocytes. Researchers showed that a minor population of CD4+ T-cells, which co-expresses the interleukin-2 receptor α-chain, could control autoreactive T-cells in vivo. Researchers state that dysfunction within regulatory cell subsets could be a significant contributor to autoimmune disease susceptibility.

Tumor-associated antigens such as NY-ESO-1 are expressed in a variety of solid tumors but absent in mature healthy tissues with the exception of germline cells. The immune system anti-cancer attack is mediated by cell lysis or induction of growth arrest through paralysis of tumor cells, the latter of which can be achieved by tumor-specific CD4+, IFNγ-producing THelpertype 1 (TH1) cells. Translation of these immune-mediated mechanisms into clinical application has been limited by availability of immune effectors, as well as the need for complexin vitroprotocols and regulatory hurdles. Here, we report a procedure to generate cancer-testis antigen NY-ESO-1-targeting CD4+TH1 cellsin vitrofor cancer immunotherapy in the clinic. After in vitro sensitization by stimulating T cells with protein-spanning, overlapping peptide pools of NY-ESO-1 in combination with IL-7 and low dose IL-2, antigen-specific T cells were isolated using IFNγ capture technique and subsequently expanded with IL-2, IL-7 and IL-15. Large numbers of NY-ESO-1-specific CD4+T cells with a TH1 cytokine profile and lower numbers of cytokine-secreting CD8+T cells could be generated from healthy donors with a high specificity and expansion potential. Manufactured CD4+T cells showed strong specific TH1-responses with IFNγ+, TNFα+, IL-2+and induced cell cycle arrest and apoptosis in tumor cells. The protocol is GMP-grade and approved by the regulatory authorities. The tumor-antigen specific CD4+TH1 lymphocytes can be adoptively transferred as a T-cell therapy to boost anticancer immunity and this novel cancer treatment approach is applicable to both T cells from healthy allogeneic donors as well as to autologous T cells derived from cancer patients. [ABSTRACT FROM AUTHOR]

Many species of bacteria use quorum sensing to sense the amounts of secreted metabolites and adapt their growth according to their population density. We asked whether similar mechanisms would operate in lymphocyte homeostasis. We investigated the regulation of the size of Interleukin-2-producing CD4 + T-cell (IL-2p) pool using different IL-2-reporter mice. We found that in the absence of either IL-2 or regulatory CD4 + T-cells (Treg) the number of IL-2p-cells increases. Administration of IL-2 decreases the number of cells of the IL-2p-cell subset and pertinently, abrogates their ability to produce IL-2 upon in vivo cognate stimulation, while increasing Treg-cell numbers. We propose that control of the IL-2p-cell numbers occurs via a quorum-sensing-like feedback loop where the produced IL-2 is sensed by both the activated CD4 + T-cell pool and by Treg-cells, which reciprocally regulate cells of the IL-2p-cell subset. In conclusion, IL-2 acts as a self-regulatory circuit integrating the homeostasis of activated and regulatory T cells as CD4 + T-cells restrain their growth by monitoring IL-2 levels thereby preventing uncontrolled responses and autoimmunity. J. Exp. Med. 2013 vol. 210(12) pp. 2707–2720. [ABSTRACT FROM AUTHOR]

The peripheral Foxp3+ Treg pool consists of naturally arising Treg (nTreg) and adaptive Treg cells (iTreg). It is well known that naive CD4+ T cells can be readily converted to Foxp3+ iTreg in vitro, and memory CD4+ T cells are resistant to conversion. In this study, we investigated the induction of Foxp3+ T cells from various CD4+ T-cell subsets in human peripheral blood. Though naive CD4+ T cells were readily converted to Foxp3+ T cells with TGF-β and IL-2 treatment in vitro, such Foxp3+ T cells did not express the memory marker CD45RO as do Foxp3+ T cells induced in the peripheral blood of Hepatitis B Virus (HBV) patients. Interestingly, a subset of human memory CD4+ T cells, defined as CD62L+ central memory T cells, could be induced by TGF-β to differentiate into Foxp3+ T cells. It is well known that Foxp3+ T cells derived from human CD4+CD25- T cells in vitro are lack suppressive functions. Our data about the suppressive functions of CD4+CD62L+ central memory T cell-derived Foxp3+ T cells support this conception, and an epigenetic analysis of these cells showed a similar methylation pattern in the FOXP3 Treg-specific demethylated region as the naive CD4+ T cell-derived Foxp3+ T cells. But further research showed that mouse CD4+ central memory T cells also could be induced to differentiate into Foxp3+ T cells, such Foxp3+ T cells could suppress the proliferation of effector T cells. Thus, our study identified CD4+CD62L+ central memory T cells as a novel potential source of iTreg. [ABSTRACT FROM AUTHOR]

The mechanisms mediating protective immunity to hepatitis C virus (HCV) infection are incompletely understood because early infection in humans is rarely identified, particularly in those individuals who subsequently demonstrate spontaneous virus eradication. We have established a large national network of patients with acute HCV infection. Here, we comprehensively examined total HCV-specific CD4+ and CD8+ T-cell responses and identified functional T-cell thresholds that predict recovery. Interestingly, we found that the presence of HCV-specific cytotoxic T lymphocytes (CTLs) that can proliferate, exhibit cytotoxicity, and produce gamma interferon does not ensure recovery, but whether these CTLs were primed in the presence or absence of CD4+ T-cell help (HCV-specific interleukin-2 production) is a critical determinant. These results have important implications for early prediction of the virologic outcome following acute HCV and for the development of novel immunotherapeutic approaches. [ABSTRACT FROM AUTHOR]

Immune function in the elderly is associated with a number of phenotypic and functional abnormalities, and this phenomenon of immune senescence is associated with increased susceptibility to infection. The immune response to pathogens frequently declines with age, but the CD8+ T-cell response to cytomegalovirus (CMV) is unusual, as it demonstrates a significant expansion over time. Here we have documented the CD4+ T-cell immune response to CMV in healthy donors of different ages. The magnitude of the CMV-specific CD4+ T-cell immune response increases from a mean of 2.2% of the CD4+ T-cell pool in donors below 50 years of age to 4.7% in donors aged over 65 years. In addition, CMV-specific CD4+ T cells in elderly donors demonstrate decreased production of interleukin-2 and less dependence on costimulation. CMV seropositivity is associated with marked changes in the phenotype of the overall CD4+ T-cell repertoire in healthy aged donors, including an increase in CD57+ expression and a decrease in CD28 and CD27 expression, a phenotypic profile characteristic of immune senescence. This memory inflation of CMV-specific CD4+ T cells contributes to evidence that CMV infection may be damaging to immune function in elderly individuals. [ABSTRACT FROM AUTHOR]

Summary We examined the proliferative and cytokine-producing activities of CD4+ T cells from young mice of the senescence-accelerated mouse strain SAMP1, which had shown markedly low T-dependent antibody-producing responses. When splenic T cells were cultured with concanavalin A (Con A), the percentage of CD4+ cells decreased earlier in SAMP1 than in C3H/He mice. At 40 hr of culture, the percentage of BrdU-labelled proliferating CD4+ cells increased strongly in C3H/He, but only slightly in SAMP1. When purified CD4+ T cells were cultured with Con A, the percentage of 5-bromo-2′-deoxyuridine (BrdU)-labelled cells peaked at around 48 hr of culture in both strains, but decreased significantly at 64 hr in SAMP1. The production of interleukin (IL)-2 but not IL-4 or interferon-γ (IFN-γ) was significantly lower in SAMP1 than in C3H/He at 48 hr of culture. IL-2 production was also markedly low in SAMP1, even under the stimulation of anti-CD3 with anti-CD28 antibodies. The frequency of cells producing IL-2 was significantly lower in SAMP1 than in C3H/He at 6–24 hr of culture with Con A. The percentage of annexin-positive and propidium iodide (PI)-negative apoptotic cells was significantly higher in SAMP1 than in C3H/He at 96 hr of culture. Exogenous IL-2 prevented the decrease in BrdU-labelled cells and the increase in apoptotic cells in the SAMP1 cell culture. These results indicate that SAMP1 CD4+ T cells cannot produce IL-2 at levels sufficient to support cell proliferation and survival. This may account for the weak T-dependent antibody response in SAMP1 mice. [ABSTRACT FROM AUTHOR]

Background: Interleukin-2 is a cytokine that regulates the proliferation and differentiation of lymphocytes. In preliminary studies, intermittent infusions of interleukin-2 led to increases in CD4 counts in patients with human immunodeficiency virus (HIV) infection and more than 200 CD4 cells per cubic millimeter. We conducted a controlled study to evaluate the long-term effects of such therapy on both CD4 counts and the viral burden. Methods: Sixty HIV-infected patients with base-line CD4 counts above 200 cells per cubic millimeter were randomly assigned to receive either interleukin-2 plus antiretroviral therapy (31 patients, 1 of whom was lost to follow-up) or antiretroviral therapy alone (29 patients). Interleukin-2 was administered every two months for six cycles of five days each, starting at a dosage of 18 million IU per day. Safety and immunologic and virologic measures were monitored monthly until four months after the last treatment cycle. Results: In patients treated with interleukin-2, the mean (±SE) CD4 count increased from 428±25 cells per cubic millimeter at base line to 916±128 at month 12, whereas in the control group, the mean CD4 count decreased from 406±29 cells per cubic millimeter to 349±41 (P<0.001). There were no significant differences between the groups in serial measurements of the plasma HIV RNA or p24 antigen concentration during the 12 months of treatment. Constitutional symptoms (fever, malaise, and fatigue) and asymptomatic hyperbilirubinemia were the chief dose-limiting toxic effects of interleukin-2 therapy. Conclusions: In patients with HIV infection and base-line CD4 counts above 200 cells per cubic millimeter, intermittent infusions of interleukin-2 produced substantial and sustained increases in CD4 counts with no associated increase in plasma HIV RNA levels. (N Engl J Med 1996;335:1350-6.) [ABSTRACT FROM AUTHOR]