TCR repertoire diversity substantially decreased as CD4+ memory T cell populations emerged following infection with either lymphocytic choriomeningitis computer virus (LCMV) or recombinant expressing the immunodominant MHC Class II-restricted epitope, GP61-80, derived from the LCMV Glycoprotein (Lm-gp61). T cells survives and populates the long-lived memory T cell pool (van Leeuwen et al., 2009). The differentiation actions that lead to RIPK1-IN-4 the formation of effector T helper-1 (Th1) cells have been studied extensively, but less is known regarding the signals that enable a subset of effector Th1 cells Mouse monoclonal to S100B to differentiate into memory cells, although CD4+ T cells fated to become memory cells can be identified during the effector response to acute contamination (Marshall et al., 2011). Identification of the signals that promote memory cell differentiation is key to understanding how activated T cells make fate decisions as well as to the design of better vaccination and immunotherapeutic strategies aimed at enhancing CD4+ memory T cell formation and function. External environmental cues, including cytokines, control the expression of transcription factors that promote T helper subset differentiation, including T-bet, Blimp-1, STAT3, STAT4 and Bcl-6 in settings of Type I cell-mediated inflammation (Eto et al., 2011; Johnston et al., 2012; Johnston et al., 2009; Nakayamada et al., 2011; Pepper et al., 2011). The extent to which these factors promote effector or memory T cell fate decisions is less clear. Some recent articles have implied potential functions for Bcl-6 and IL-21 in the differentiation and formation of CD4+ central memory T cells, along with an opposing role for interleukin-2 (IL-2)-driven STAT5 activation in driving effector-memory Th1 cell differentiation (Crotty et al.; Johnston et al., 2012; Luthje et al., 2012; Pepper et al., 2011; Weber et al., 2012a). Cell-intrinsic differentiation cues, in particular those dependent on T cell receptor (TCR) binding and signaling, also play a clear role in many aspects of CD4+ T cell differentiation. For CD4+ T cells, the strength of TCR-mediated signaling progressively drives effector differentiation and survival (Gett et al., 2003), and repeated activation selectively enriches for responding CD4+ T cells with high avidity TCRs (Savage et al., 1999). Additionally, several days of exposure to antigen are required for full differentiation of effector (Obst et al., 2005; Williams and Bevan, 2004) and memory (Jelley-Gibbs et al., 2005) CD4+ T cells. The nature of the TCR stimulus also influences the differentiation of T helper subsets, including Th1, RIPK1-IN-4 T helper 2 (Th2), T follicular helper (Tfh) and regulatory T (Treg) cells (Brogdon et al., 2002; Fazilleau et al., 2009; Lee et al., 2012; Leitenberg and Bottomly, 1999; Moran et al., 2011; Olson et al., 2013). Low immunizing doses can result in the generation of CD4+ memory T cells with high affinity TCRs (Rees et al., 1999), and secondary responses are characterized by the emergence of secondary CD4+ T cell responders with high avidity for antigen (Savage et al., 1999). An additional study reports defects in memory cell formation related to na?ve precursor frequency (Blair and Lefrancois, 2007). Based on the combined evidence, one can reasonably conclude that high avidity CD4+ T cells are progressively selected in the presence of antigen. However, it is unknown how TCR-mediated differentiation signals during the main T cell response might influence long-term fate once antigen is usually cleared. The role RIPK1-IN-4 of sustained TCR interactions with antigenic peptide bound to MHC Class II (pMHCII) in the specification of memory T cell fate has not been directly determined. We previously showed that not all clones that participate in the effector.