Antigen Presentation and T Cell Development in H2-M-Deficient Mice

Abstract

HLA-DM (DM) facilitates peptide loading of major histocompatibility complex class II molecules in human cell lines. Mice lacking functional H2-M, the mouse equivalent of DM, have normal amounts of class II molecules at the cell surface, but most of these are associated with invariant chain-derived CLIP peptides. These mice contain large numbers of CD4+ T cells, which is indicative of positive selection in the thymus. Their CD4+ cells were unresponsive to self H2-M-deficient antigen-presenting cells (APCs) but were hyperreactive to wild-type APCs. H2-M-deficient APCs failed to elicit proliferative responses from wild-type T cells.

Relaxed DM Requirements During Class II Peptide Loading and CD4+ T Cell Maturation in BALB/c Mice

“…Selective loss of class II conformational epitopes in human somatic variants (38) and mice lacking DM function (23,24,39) closely correlates with CLIP occupancy. In contrast, considerable evidence suggests DM activities are nonessential for conformational maturation of other class II allelic products, but there are also contradictory results in the literature (18 -21, 30).…”

“…The class II chain specificities (36,37) and Ii chain influences affecting expression of these conformational epitopes (10,34) have been extensively discussed. Rabbit antisera specific for determinants located in the cytoplasmic tails of the ␣-and ␤-chains were generously provided by Ronald N. Germain (YFMYSKLRVQKSTWERG), bacteriophage repressor cI peptide P [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] (LEDARRLKAIYEKKK), SWM 129 -153 GAMNKALELFRKDI-AAKYKELGYQG, the truncated variant of moth cytochrome 88 -103 previously described as DASP KKANELIAYLKQATK, the Ii chain 85-101 KPVSQMRMATPLLMRPM peptides, and biotin-conjugated variants were purchased from Quality Controlled Biochemicals (Hopkinton, MA).…”

“…The striking accumulation of A b /CLIP complexes alongside severely reduced peptide-loading capabilities strongly argues DM activity is required to mediate CLIP release and promote occupancy by diverse peptides under physiological conditions in normal APCs. As judged by the gain of reactivity toward wild-type class II molecules, mature CD4 ϩ T cells exclusively selected on A b /CLIP complexes exhibit somewhat incomplete tolerance toward natural self-peptides (22)(23)(24). Considerable evidence suggests these animals express a semidiverse TCR repertoire (25-28).…”

“…It also seems likely that DM actions demonstrated via these complementation assays could be influenced by many additional experimental parameters, such as abnormal expression levels and functional contributions by recipient cell lines, making it difficult to assess the significance of these observations. Current thinking about the class II pathway has been strongly influenced by studies of DM mutant mice (22)(23)(24). The loss of DM function disrupts conventional Ag presentation and causes complex defects with respect to selection of mature CD4 ϩ T cells.…”

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

“…Although crystallographic studies have not found any evidence for this possibility (58,60), studies with conformation-dependent Abs have suggested that peptide binding can affect the conformation of MHC class I (61, 62) and class II (43,44,59,(63)(64)(65) molecules and that such subtly altered conformations can affect recognition by TCRs (57,(65)(66)(67). Our observation that none of the hybrids reactive with A b EpIi Ϫ cells recognized H2-DM-deficient cells, and vice versa (Table I), is consistent with this idea.…”