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Human CD4 residue Phe 43 is critical for repertoire development and maturation of MHC class II restricted CD4 single‐positive T lineage cells in vivo

To determine the functional significance of structural alteration of CD4‐MHC class II interaction in vivo, two human (h)CD4‐transgenic (tg) mice were established on a murine (m)CD4– / – H‐2b background. The MHC class II binding‐competent hCD4 (R240AhCD4) rescues the number and helper activity of hCD4+CD8– single‐positive (SP) mature T cells in mCD4– / – mice. In contrast, the MHC class II binding‐deficient F43I hCD4 mutant cannot facilitate normal differentiation of double‐positive thymocytes to CD4+CD8– SP thymocytes. Hence, only 20 – 25 % of CD4+CD8– SP T cells found in wild‐type or R240A hCD4tg mice are generated, with resultant diminished helper responses. Differentiation of F43I hCD4 SP T cells is MHC class II but not class I dependent as demonstrated by crossing F43I hCD4tg mice onto MHC‐deficient mice. These cells show a different pattern of TCR Vα and Vβ gene usage relative to comparable R240A hCD4 SP T cells from R240 AhCD4tg animals. Expression of activation markers including CD25 and CD69 on F43I hCD4 SP T cells suggests that autoreactive specificites may not have been eliminated intrathymically. Collectively, the results show that CD4‐MHC class II interaction significantly influences intrathymic repertoire selection.