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CD4 T cell-mediated help to CD8 T cells and B cells is a critical arm of the adaptive immune system required for control of pathogen infection. CD4 T cells express cytokines and co-stimulatory molecules that support a sustained CD8 T cell response and also enhance generation of protective antibody by germinal center B cells. However, the molecular components that modulate CD4 T cell functions in response to viral infection or vaccine is incompletely understood. Here we demonstrate that inactivation of the signaling adaptor CD2-associated protein (CD2AP) promotes CD4 T cell differentiation towards the follicular helper lineage, leading to enhanced control of viral infection by augmented germinal center response in chronic lymphocytic choriomeningitis virus (LCMV) infection. The enhanced follicular helper differentiation is associated with extended duration of TCR signaling and enhanced cytokine production of CD2AP-deficient CD4 T cells specifically under TH1 conditions, while neither prolonged TCR signaling nor enhanced follicular helper differentiation was observed under conditions that induce other helper effector subsets. Despite the structural similarity between CD2AP and the closely related adaptor protein CIN85, we observed defective antibody-mediated control of chronic LCMV infection in mice lacking CIN85 in T cells, suggesting non-overlapping and potentially antagonistic roles for CD2AP and CIN85. These results suggest that tuning of TCR signaling by targeting CD2AP improves protective antibody responses in viral infection. [ABSTRACT FROM AUTHOR]

The early events that initiate inflammation in the adipose tissue during obesity are not well defined. It is unclear whether the recruitment of CD8 T cells to the adipose tissue during onset of obesity occurs through antigen-dependent or -independent processes. We have previously shown that interaction between NKG2D (natural-killer group 2, member D) and its ligand Rae-1ε is sufficient to recruit cytotoxic T lymphocytes to the pancreas and induce insulitis. Here, we tested whether NKG2D–NKG2D ligand interaction is also involved in obesity-induced adipose tissue inflammation and insulin resistance. We observed a significant induction of NKG2D ligand expression in the adipose tissue of obese mice, especially during the early stages of obesity. However, mice lacking NKG2D developed similar levels of insulin resistance and adipose tissue inflammation compared to control mice when placed on a high-fat diet. Moreover, overexpression of Rae-1ε in the adipose tissue did not increase immune cell infiltration to the adipose tissue either in the setting of a normal or high-fat diet. These results indicate that, unlike in the pancreas, NKG2D–NKG2D ligand interaction does not play a critical role in obesity-induced inflammation in the adipose tissue. [ABSTRACT FROM AUTHOR]

The mammalian target of rapamycin (mTOR) kinase is a critical regulator of the differentiation of helper and regulatory CD4+ T cells, as well as memory CD8+ T cells. In this study, we investigated the role of the ERK signaling pathway in regulating mTOR activation in T cells. We showed that activation of ERK following TCR engagement is required for sustained mTOR complex 1 (mTORC1) activation. Absence of kinase suppressor of Ras 1 (KSR1), a scaffold protein of the ERK signaling pathway, or inhibition of ERK resulted in decreased mTORC1 activity following T cell activation. However, KSR1-deficient mice displayed normal regulatory CD4+ T cell development, as well as normal memory CD8+ T cell responses to LCMV and Listeria monocytogenes infection. These data indicate that despite its role in mTORC1 activation, KSR1 is not required in vivo for mTOR-dependent T cell differentiation. [ABSTRACT FROM AUTHOR]

As with all scientific disciplines, advances in immunology are driven by experimental observations. Observations yield facts that can be integrated into hypotheses and theoretical models that are amenable to further experimental tests. The ultimate product of this iterative process of making observations and theoretical model building is mechanistic understanding. The creation of models has been essential in many important advances in biology; the most famous example is Watson and Crick's model for the structure of DNA. Exploration of ideas with conceptual models before the availability of experimental data has also led to the development of some of the basic paradigms of immunology. In the past three decades, advances in cell culture techniques, immunochemistry, recombinant DNA methodology, X-ray crystallography and the use of transgenic mice have enabled the explanation of diverse immunological phenomena in terms of protein structure and specific biochemical events. However, there are some recent indications that quantitative theoretical models can partner fruitfully with cellular experiments to substantially advance the understanding of molecular mechanisms that underlie key events such as T cell activation, T cell migration and thymocyte selection.

Although the Src family tyrosine kinase Lck is essential for T cell receptor (TCR) signaling, whether or how Lck is activated is unknown. Using a phosphospecific antiserum to Lck, we show here that Lck becomes autophosphorylated when T cells are stimulated by antigen-presenting cells (APCs). We found that TCR cross-linking alone could not stimulate Lck autophosphorylation and CD45 was not required for this process. Instead, the T cell accessory molecules CD4 and CD28 cooperated to induce autophosphorylation of Lck. CD4 recruited Lck to the T cell?APC interface, whereas CD28 sustained Lck activation. These data show how the multiple interactions afforded by the immunological synapse drive efficient and highly specific signaling. [ABSTRACT FROM AUTHOR]

The article discusses two reports within the issue regarding immunology research in which both scientific teams demonstrate a part of the mechanism that alerts sentinel cells embedded in the skin and mucosa that it has been breached by a pathogen. Topics include an overview of the physiology of skin and various skin proteins, including the immunoglobulin superfamily (IgSF), which facilitates the transient opening of epithelial barriers to allow the passage of cells in tight junctions, and the junctional adhesion molecule-like proteins (JAMLs), which facilitates neutrophil chemotaxis across endothelial cells. Also discussed is the sentinel skin cell γδ, which is an epidermal T cell that responds to injury and infection when stimulated by a cellular adhesion protein.

Reports that immunological and neurological synapses use a common molecule called agrin. T cell activation; Recruitment of lipid rafts; Deglycosylation of extracellular ligands.

I cells integrate and transduce the key signals necessary to mount an appropriate immune response. To do this, they rely on both secreted factors as well as physical cell-cell contact. Much attention has focused on the organization of proteins at the contact area between a T cell and an antigen-presenting cell, known as the immunological synapse. It has been shown in vitro that proteins segregate into two distinct regions within this contact area, a central area referred to as the c-SMAC, where the I cell receptor and associated signaling molecules are enriched, and a peripheral region called the p-SMAC containing LFA- 1 and the scaffolding protein talin. Whether or not these structures form in vivo and how they function in T cell activation remain issues of great interest, Here, we review recently published work and propose several possible functions for the role of the c-SMAC in T cell activation. [ABSTRACT FROM AUTHOR]

Four non-enzymatic proteins form the structural core of the TCR signaling machinery, linking antigen-receptor activation to signaling. These four proteins, each with well defined protein–protein interaction domains, include three ‘scaffolds’ (LAT, SLP-76 and SLAP-130/Fyb/ADAP and a ‘pure adaptor’ (GADS). The biological functions of many distinct protein–protein interaction domains have been dissected through a methodological series of knockout and reconstitution experiments. In reviewing these recent advances, we attempt to address two questions often asked by immunologists not familiar with the field: what do scaffolds/adaptors/linkers do; and what do these terms mean? [Copyright &y& Elsevier]

Summary: The role of the center of the immunological synapse (the central supramolecular activation cluster or cSMAC) is controversial. One model suggests that the role of the cSMAC depends on antigen quality and can both enhance signaling and receptor downregulation, whereas a second model proposes that the sole function of the cSMAC is to downregulate signaling. An important distinction between the models is whether signaling occurs in the cSMAC. Here, we demonstrate that at early time points, signaling occurs outside the cSMAC, but occurs in the cSMAC at later time points. Additionally, we show that cSMAC formation enhances the stimulatory potency of weak agonists for the TCR. Combined with previous studies showing that cSMAC formation decreases the signaling by strong agonists, our data support a model proposing that signaling and receptor degradation both occur in the cSMAC and that the balance between signaling and degradation in the synapse is determined by antigen quality. [Copyright &y& Elsevier]