To become activated, T cells must efficiently recognize antigen-presenting cells or target cells through several complex cytoskeleton-dependent processes, including integrin-mediated adhesion, immunological-synapse formation, cellular polarization, receptor sequestration and signalling. The actin and microtubule systems provide the dynamic cellular framework that is required to orchestrate these processes and ultimately contol T-cell activation. Here, we discuss recent advances that have furthered our understanding of the crucial importance of the T-cell cytoskeleton in controlling these aspects of T-cell immune recognition.

These data reveal a role for WAVE2 in regulating multiple pathways leading to T cell activation. In particular, this work shows that WAVE2 is a key component of the actin regulatory machinery in T cells and that it also participates in linking intracellular calcium store depletion to calcium release-activated calcium (CRAC) channel activation.

HS1, the leukocyte-specific homolog of cortactin, regulates F-actin in vitro and is phosphorylated in response to TCR ligation, but its role in lymphocyte activation has not been addressed. We demonstrate that HS1-deficient T cells fail to accumulate F-actin at the immune synapse (IS) and, upon TCR ligation, form actin-rich structures that are disordered and unstable. Early TCR activation events are intact in these cells, but Ca2+ influx and IL-2 gene transcription are defective. Importantly, HS1 tyrosine phosphorylation is required for its targeting to the IS and for its function in regulating actin dynamics and IL-2 promoter activity. Phosphorylation also links HS1 to multiple signaling proteins, including Lck, PLCgamma1, and Vav1, and is essential for the stable recruitment of Vav1 to the IS. Taken together, our studies show that HS1 is indispensable for signaling events leading to actin assembly and IL-2 production during T cell activation.

CD8+ T cells activated during viral infection migrate to infected skin in an antigen-independent manner. Local recognition of antigens drives the differentiation into Trm CD8+ T cells.

Summary CD8+ T cells confer host protection through T cell receptor (TCR)-mediated recognition of foreign antigens presented by infected cells. Thus, generation of CD8+ T cell populations with high antigen sensitivity is critical for efficient pathogen clearance. Besides selection of high affinity TCR, the molecular mechanisms regulating the antigen sensitivity of CD8+ T cells remain poorly defined. Herein, we have demonstrated that the antigen sensitivity of effector and memory CD8+ T cells is dynamically regulated and can be tuned by the pathogen-induced inflammatory milieu independently of selection of cells with higher affinity TCR. Mechanistically, we have demonstrated that the signal transduction capacity of key TCR proximal molecules was enhanced by inflammatory cytokines, which reduced the antigen density required to trigger antimicrobial functions. Dynamic tuning of CD8+ T cell antigen sensitivity by inflammatory cytokines likely optimizes immunity to specific pathogens while minimizing the risk of immunopathology at steady state.

SUMMARY Infection or vaccination confers heightened resistance to pathogen re-challenge due to quantitative and qualitative differences between naïve and primary memory T cells. Herein, we show that secondary (boosted) memory CD8+ T cells were better than primary memory CD8+ T cells in controlling some, but not all acute infections with diverse pathogens. However, secondary memory CD8+ T cells were less efficient than an equal number of primary memory cells at preventing chronic LCMV infection and are more susceptible to functional exhaustion. Importantly, localization of memory CD8+ T cells within lymph nodes, which is reduced by antigen re-stimulation, was critical for both viral control in lymph nodes and for the sustained CD8+ T cell response required to prevent chronic LCMV infection. Thus, repeated antigen-stimulation shapes memory CD8+ T cell populations to either enhance or decrease per cell protective immunity in a pathogen-specific manner, a concept of importance in vaccine design against specific diseases.

WAVE2 regulates T cell receptor (TCR)–stimulated actin cytoskeletal dynamics leading to both integrin clustering and affinity maturation. Although WAVE2 mediates integrin affinity maturation by recruiting vinculin and talin to the immunological synapse in an Arp2/3-dependent manner, the mechanism by which it regulates integrin clustering is unclear. We show that the Abl tyrosine kinase associates with the WAVE2 complex and TCR ligation induces WAVE2-dependent membrane recruitment of Abl. Furthermore, we show that WAVE2 regulates TCR-mediated activation of the integrin regulatory guanosine triphosphatase Rap1 via the recruitment and activation of the CrkL–C3G exchange complex. Moreover, we demonstrate that although Abl does not regulate the recruitment of CrkL–C3G into the membrane, it does affect the tyrosine phosphorylation of C3G, which is required for its guanine nucleotide exchange factor activity toward Rap1. This signaling node regulates not only TCR-stimulated integrin clustering but also affinity maturation. These findings identify a previously unknown mechanism by which the WAVE2 complex regulates TCR signaling to Rap1 and integrin activation.

Trafficking of CD8 T cells, in both the steady-state and during episodes of infection or inflammation, is a highly dynamic process and involves a variety of receptor-ligand interactions. A thorough, mechanistic understanding of how this process is regulated could potentially lead to disease prevention strategies, through either enhancing (for infectious diseases or tumors) or limiting (for autoimmunity) recruitment of antigen-specific CD8 T cells to areas of tissue inflammation. As CD8 T cells transition from naive to effector to memory cells, changes in gene expression will ultimately dictate anatomical localization of these cells in vivo. In this article, we discuss recent advances in understanding how antigenic stimulation influences expression of various trafficking receptors and ligands, and how this determines the tissue localization of CD8 T cells.