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Section of Immunobiology, Yale University School of Medicine, and Howard Hughes Medical Institute, New Haven, CT 06520
The use of mutant mice expressing a normal MHC class II molecule
surface level but a severely restricted self-peptide diversity
(H-2M
-/-) previously revealed that T cells carrying
the E52–68–I-Ab complex-specific 1H3.1 TCR
rely on self-peptide(s) recognition for both their peripheral
persistence in irradiated hosts and their intrathymic positive
selection. Here, we identify E52–68 structurally
related self-peptide(s) as a major contributor to in vivo positive
selection of 1H3.1 TCR-transgenic thymocytes in
I-Ab+/I-E- mice. This is demonstrated by
the drastic and specific reduction of the TCR high thymocyte population
in 1H3.1 TCR-transgenic (Tg) mice treated with the
E52–68–I-Ab complex-specific
Y-Ae mAb. Self-peptide(s) recognition is also driving
the maturation of T cells carrying a distinct MHC class II-restricted
specificity (the E6 
TCR), since positive
selection was also deficient in E6 TCR Tg
H-2M-/- thymi. Such a requirement for recognition of
self-determinants was mirrored in the periphery; E6 TCR
Tg naive T cells showed an impaired persistence in both
H-2M-/- and I-Ab-/-
irradiated hosts, whereas they persisted and slowly cycled in wild-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
surface expression of other markers such as CD62L remained unaltered.
Collectively, these observations indicate that maturation and
maintenance of naive MHC class II-restricted T cells are self-oriented
processes.
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