CD5 levels define functionally heterogeneous populations of naive human CD4+ T cells

Studies in murine models show that subthreshold TCR interactions with self-peptide are required for thymic development and peripheral survival of naive T cells. Recently, differences in the strength of tonic TCR interactions with self-peptide, as read-out by cell surface levels of CD5, were associated with distinct effector potentials among sorted populations of T cells in mice. However, whether CD5 can also be used to parse functional heterogeneity among human T cells is less clear. Our study demonstrates that CD5 levels correlate with TCR signal strength in human naive CD4(+) T cells. Further, we describe a relationship between CD5 levels on naive human CD4(+) T cells and binding affinity to foreign peptide, in addition to a predominance of CD5(hi) T cells in the memory compartment. Differences in gene expression and biases in cytokine production potential between CD5(lo) and CD5(hi) naive human CD4(+) T cells are consistent with observations in mice. Together, these data validate the use of CD5 surface levels as a marker of heterogeneity among human naive CD4(+) T cells with important implications for the identification of functionally biased T- cell populations that can be exploited to improve the efficacy of adoptive cell therapies.