Impact of Time on the Size, Shape and Effector Responses of Cd4⁺ T Cells

T cells discriminate self from foreign peptides presented in the context of self-major histocompatibility complex (pMHC) molecules via clonotypic T cell receptors (TCRs). CD8⁺ T cell recognition and responsiveness to foreign pMHC is known to diminish over the lifespan, which is consistent with gradual thymic involution over time. It is further supported by experimental evidence that restricting the diversity of class I MHC peptides during positive and negative selection results in selection of fewer CD8⁺ T cells that are highly specific for pMHC. How the affinity of the CD4⁺ T cell compartment for self-pMHC, and its capacity to bind foreign-pMHC change over the lifespan are fundamental aspect of T cell biology that remain largely unexplored. Experimentally restricting thymic selection is known to allow degenerate CD4⁺ T cells to develop. This suggests that they might accumulate in the CD4⁺ T cell compartment over time. We report that, while old mice (18-22 months) contain fewer CD4⁺ T cells than adults (8-12 weeks), those that remain have a higher intrinsic affinity for self-pMHC. Old mice also have more cells that bind distinct foreign-pMHCs, either alone or in combination. The numerical increase of these subsets with age directly correlates with their affinity for self-pMHC. However, no relationship was observed between affinity for self-pMHC and responsiveness to foreign-pMHC. These data demonstrate that the CD4⁺ T cell compartment preferentially accumulates promiscuous constituents with age as a consequence of higher affinity T cell receptor interactions with self-pMHC. These results have important implications for the design of immunotherapeutics targeting CD4⁺ T cells to improve immunity in older adults.Release after 4-May-201