Deficient Positive Selection of CD4 T Cells in Mice Displaying Altered Repertoires of MHC Class II–Bound Self-Peptides

Abstract

The role of self-peptides in positive selection of CD4+ T cells has been controversial. We show that some self-peptides are presented by the MHC class II molecule I-A(b) in mice lacking Ii or H-2M but not in mice expressing a transgene-encoded peptide fused to I-A(b). In experiments using specific antibodies to block selection, these low-abundance self-peptides were implicated in the positive selection of some CD4+ T cells in H-2M-/- mice. However, all three mutant backgrounds failed to positively select two class II-restricted transgenic T cell receptors. Our findings suggest that minor components of the self-peptide repertoire can contribute to positive selection of a significant number of CD4+ T cells. In addition, the data suggest that T cell receptor repertoires selected in wild-type mice and in mice displaying limited spectra of self-peptides are distinct.

Proliferating CD4+ T Cells Undergo Immediate Growth Arrest upon Cessation of TCR Signaling In Vivo

“…TEa CD4 ϩ T cells express Thy1.1 (CD90.1) and V␤6 and recognize the I-E d ␣-chain peptide 52-68 (pE␣) 3 presented by I-A b (19). Thy1.1-C57BL/6NCr (B6) (H-2 b ) mice were purchased from Charles River Laboratories through a contract with the National Cancer Institute of the National Institutes of Health, and were used as syngeneic recipient mice for adoptive transfer studies.…”

“…To develop a model system that would give us control over the kinetics of TCR occupancy in vivo, we made use of the Y-Ae mAb that specifically recognizes pE␣/I-A b complexes and competes for binding with the TCR on the TEa T cells (19,21). One million CFSE-labeled CD4 ϩ TEa T cells were again adoptively transferred into B6 mice and challenged with EaRFP/LPS for a period of 120 h. Y-Ae mAb was also administered to the mice at various time points following the Ag injection.…”

Positive Selection Is Limited by Available Peptide-Dependent MHC Conformations

“…This argues that peptide diversity, although present in the normal situation, is not important in T cell development. However, it has recently been shown that at least two of these approaches did not truly limit the peptide presentation to a single face (19,20). Additionally, the small percentage of MHC molecules presenting diverse self peptides was shown to be important in selecting T cells.…”

The Alloreactive and Self-Restricted CD4+ T Cell Response Directed Against a Single MHC Class II/Peptide Combination

“…These clonal hybrids (nearly 500) were then tested for reactivity with APC from wild-type B6, H2-DM-deficient, Ii-deficient, A b EpIi Ϫ , and MHC class II-deficient mice (all from the H2 b haplotype). MHC class II molecules in these mice display varying degrees of class II cell-surface expression levels and peptide diversity: in B6 mice A b class II molecules are bound by a wide gemish of self-peptides; in H2-DM-deficient mice, A b molecules are expressed at normal levels and are mostly bound by a peptide, CLIP, derived from the MHC class II-associated Ii chain (41, 43, 44), but some contamination by non-CLIP peptides has been noted (45,46); in Ii-deficient mice, A b surface expression is reduced ϳ10-fold, and these molecules are thought to be occupied by low-affinity peptides (40,(47)(48)(49); in A b EpIi Ϫ mice, A b surface expression is reduced ϳ10-fold, and these complexes are bound by Ep (7); finally, MHC class II-deficient mice lack class II surface expression altogether (42,50). The reactivity of these hybrids was graded strong, weak, or none, when IL-2 produced by the hybrids was Ͼ50, 10 -50, or Ͻ10%, respectively, of the IL-2 produced when the hybrids were stimulated with wild-type B6 cells (Table I).…”

“…not all class II molecules in these mice are bound by CLIP (45,46). The experimental system used here does not have this limitation, because it is well-established that A b EpIi Ϫ mice express only a single peptide species (Ep) on their class II molecules (7,45).…”