Development of CD4⁺T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms

Abstract

Most ␣␤ T cells belong to one of the two lineages defined by the mutually exclusive expression of CD8 or CD4 coreceptors, which bind MHC class I and class II molecules, respectively. Because the binding of the coreceptors to MHC molecules stabilizes weak interactions between TCRs and peptide-MHC (pMHC) complexes, CD8 ϩ T cells are MHC class I-restricted whereas CD4 ϩ T cells are MHC class II-restricted. The concordance of CD4 or CD8 lineage development with specificity for class I or II MHC is established during differentiation of CD4 ϩ CD8 ϩ double-positive (DP) thymocytes in the thymus by a process referred to as positive selection (4). Whether a DP thymocyte differentiates into a CD4 ϩ or CD8 ϩ T cell depends on differences in TCR signaling as a result of interactions among TCR, coreceptors, and self-peptide-MHC (self-pMHC) complexes (5-8).Many TCRs are known to interact not only with self-but also with foreign MHC molecules (alloreactivity). Among the bestdocumented examples is the recognition of different pMHC complexes by a TCR called 2C (9). The 2C TCR was derived from a CD8 ϩ cytotoxic T lymphocyte (CTL) clone from an H-2 b mouse (BALB.B) that was injected with H-2 d cells (10, 11). The 2C TCR reacts with L d in association with two overlapping peptides QL-SPFPFDL (QL9) and p2Ca derived from ␣-ketoglutarate dehydrogenase (10,12,13). The 2C TCR is also alloreactive to K bm3 in association with the dEV8 peptide derived from NADHubiquinone oxoreductase (14,15). By constructing transgenic mice expressing the 2C TCR and crossing the TCR transgene onto different H-2 backgrounds, it was shown that the positive selecting MHC for the 2C T cells is K b (16,17). Among the naturally derived peptides recognized by the 2C TCR in association with L d and K bm3 , p2Ca and dEV8 bind weakly to K b and behave as weak agonists (18). However, several strong agonist peptides have been identified in combinatorial libraries to associate with K b and activate the 2C T cells (19). Among them, SIYRYYGL (SIY) has been extensively characterized. In addition to recognizing various peptides in association with MHC class I L d , K bm3 , and K b molecules, the 2C TCR was also shown recently to recognize a nonclassical class I molecule, leading to differentiation of CD8 ϩ T cells that home to the intestine during fetal and neonatal development (20).The ability of a given TCR to interact with multiple MHC molecules, especially both class I and class II, can have a significant influence on the development of CD4 versus CD8 T cells. For example, the HY TCR nominally recognizes class I D b for CD8 T cell development but also interacts with class II I-A b for CD4 T cell development (21). Similarly, the HA and AND TCRs nominally interact with class II MHC for CD4 T cell development but also promote the development of CD8 T cells on either the RAG Ϫ/Ϫ or the CD4 Ϫ/Ϫ plus TCR␣ Ϫ/Ϫ background (22, 23). The development of CD8 HA or AND transgenic T cells was shown to require the interaction of the TCRs with both class I and class II MHC molecules....

Characterization of tumor antigen peptide-specific T cells isolated from the neoplastic tissue of patients with gastric adenocarcinoma

“…Similar proportions of GCAA peptide-speciWc T cell clones were derived from CD8 + (18%) and CD4 + (15%) [5,12,37,48]. Accordingly, in our present studies we have found that a restricted number (one or two per patient) of speciWc CD4 + T cell clones showed an HLA class I-restricted response to GCAA peptides.…”

Stage-dependent reactivity of thymocytes to self-peptide–MHC complexes

“…2 and data not shown) (14) and (ii) there are differences in the intensity with which various TCRs react with self-pMHC complexes. Thus, 2C T cells and thymocytes recognize ubiquitously expressed mitochondrial peptide-K b complexes (35)(36)(37)(38), and, like male-specific HY TCR ϩ cells in male mice (39), they may be more reactive with self-pMHC than T cells that express other TCR transgenes (5).…”

“…At least two mechanisms contribute to these mismatches (4,5). In TCR-transgenic mice that express recombination-activating genes (RAG ϩ ), the absence of allelic exclusion of the TCR ␣ genes can lead to expression in the same T cell of two TCRs, the transgenic ␣␤ TCR and another TCR, consisting of the transgenic TCR ␤ chain and an endogenous TCR ␣ chain.…”

“…TCRcoreceptor mismatches found in TCR-transgenic RAG Ϫ/Ϫ mice are particularly significant because they show that a single TCR can recognize both pMHC-I and pMHC-II complexes despite the many differences between peptides associated with class I and class II MHC molecules and the MHC molecules themselves (6). That this level of degeneracy in antigen (pMHC) recognition is not unusual is evident from its having been detected, to varying extents, in 22 of 24 different TCR-transgenic RAG Ϫ/Ϫ mouse lines reported in the literature (5).…”

“…Furthermore, in 2C TCR-transgenic mice on the H-2 b [C57BL/6 (B6)] and RAG Ϫ/Ϫ backgrounds (referred to as 2C ϩ RAG Ϫ/Ϫ mice), this receptor was found on some T cells that express only CD4. This mismatch implied that the 2C TCR might also recognize pMHC-II, and, indeed, the CD4 ϩ 2C T cells failed to develop in 2C ϩ RAG Ϫ/Ϫ mice that were deficient in either class II MHC (I-A bϪ/Ϫ ) or class I MHC [transporters associated with antigen processing (TAP) Ϫ/Ϫ ], suggesting that pMHC-II as well as pMHC-I are recognized and that both are required for the development of the CD4 ϩ 2C T cells (5).…”