Experimentally, however, it is often difficult to discriminate direct effects of antigenic stimulation on recruitment processes from indirect effects CH5424802 in vivo where a few antigen-specific T cells (‘pioneer

cells’60) are required to boost (non-specific) recruitment of T cells into the tissue. Costimulatory signals (such as those mediated by CD28) delivered to T cells, in conjunction with TCR engagement, are required to sustain T-cell division, differentiation and survival.61–63 Negative costimulators [such as cytotoxic T-lymphocyte antigen 4 (CTLA-4)] counteract these effects, thus promoting homeostatic mechanisms and preventing autoimmunity. These costimulators have been shown to regulate adhesion molecules and intracellular mediators of cytoskeletal rearrangement in vitro.64–70 In vivo, CD28-mediated signals promote the localization of T cells to target tissue following priming. A prominent feature of CD28-deficient immune responses is the inefficient localization of primed T cells to non-lymphoid antigenic sites.61,71,72 We recently reported that intact CD28 signalling is required for primed T cells to leave lymphoid tissue and migrate to antigenic

sites following priming.73 buy BVD-523 TCR-transgenic T cells carrying a mutation in the cytoplasmic tail of CD28 (CD28Y170F) that abrogates phosphatidylinositol-3-kinase (PI3K) recruitment, without leading to defects in clonal expansion,74 failed to localize to target tissue following priming. The mechanism by which CD28 promotes migration of primed T cells to target tissue is unclear. CD28 does not appear to directly mediate adhesion,75 but may favour primed T-cell migration to non-lymphoid tissue by inducing integrin-mediated adhesion.73 The long-term effect of CD28-mediated signals on T-cell migration73 suggests that additional mechanisms, such as transcriptional regulation of chemokine

receptor expression,76 are likely to be involved. Despite sharing these adhesion-inducing and pro-migratory properties in vitro,77 CTLA-4-mediated signals MycoClean Mycoplasma Removal Kit lead to effects antagonistic to those induced by CD28 on T-cell migration in vivo. CTLA-4 ligation reduced conjugate formation with cognate DCs and their retention in lymph nodes in response to antigen, suggesting that CTLA-4 engagement may limit the expansion of specific T cells by reducing their cumulative interactions with cognate DCs. In addition, tissue infiltration by a murine HY-specific H2-Kk-restricted T-cell clone was abrogated by CTLA-4 ligation,73 suggesting that CTLA-4 engagement can antagonize recruitment of primed T cells to target tissue mediated by antigen-induced signals. A number of costimulatory molecules other than CD28 and CTLA-4 have been implicated in the regulation of memory T-cell migration.