On the self-referential nature of naive MHC class II-restricted T cells

The use of mutant mice expressing a normal MHC class II molecule surface le vel but a severely restricted self-peptide diversity (H-2M alpha (-/-)) pre viously revealed that T cells carrying the E alpha (52-68)-I-A(b) complex-s pecific 1H3.1 TCR rely on self-peptide(s) recognition for both their periph eral persistence in irradiated hosts and their intrathymic positive selecti on. Here, we identify E alpha (52-68) structurally related self-peptide(s) as a major contributor to in vivo positive selection of 1H3.1 TCR-transgeni c thymocytes in I-A(b+)/I-E alpha (-) mice. This is demonstrated by the dra stic and specific reduction of the TCR high thymocyte population in 1H3.1 T CR-transgenic (Tg) mice treated with the E alpha (52-68)-I-A(b) complex-spe cific Y-Ae mAb, Self-peptide(s) recognition is also driving the maturation of T cells carrying a distinct MHC class H-restricted specificity (the E al pha (6) alpha beta TCR), since positive selection was also deficient in E a lpha (6) TCR Tg H-2M alpha (-/-) thymi. Such a requirement for recognition of self-determinants was mirrored in the periphery; E alpha (6) TCR Tg naiv e T cells showed an impaired persistence in both H-2M alpha (-/-) and I-A(b )beta (-/-) irradiated hosts, whereas they persisted and slowly cycled in w ild-type recipients. This moderate self-peptide(s)-dependent proliferation was associated with a surface phenotype intermediate between those of naive and activated/memory T cells; CD44 expression was up-regulated, but surfac e expression of other markers such as CD62L remained unaltered. Collectivel y, these observations indicate that maturation and maintenance of naive MHC class II-restricted T cells are self-oriented processes.