Low‐avidity recognition by CD4⁺ T cells directed to self‐antigens

Abstract

Self-reactive T cells populate the peripheral immune system, and likely form the reservoir from which autoreactive cells are derived. We analyzed a panel of self and non-self peptides presented by HLA-DR4, a class II molecule associated with autoimmunity, by immunization of mice transgenic for HLA-DR4. Significant structural avidity for T cell recognition, as measured by MHC class II tetramer binding to CD4 + T cells was only observed in mice immunized with the non-self antigens. T cell hybridomas were generated from mice immunized with the naturally processed self-peptide hGAD65 (552-572) and also from mice immunized with an influenza-derived non-self epitope (HA 306-318). T cells specific for the self peptide failed to bind tetramers and exhibited low functional avidity as measured by the peptide concentration required to reach half-maximum proliferation values. In contrast, T cells specific for the non-self HA (306-318) peptide exhibited high structural and functional avidity profiles. As recently described in studies of murine CD8 + T cell function, the predominance of low avidity recognition of self-peptide epitopes may be a characteristic feature of CD4 + T cells responding to autoantigens.

Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

“…The low-avidity TCR-MHC͞peptide interaction may account for the low-level IFN-␥ production and protection against diabetes. In line with this possibility, some TCR-transgenic models of ␤-islet-specific autoimmunity have revealed that low levels of transgenic TCR expression tend to exert a diabetes-protective effect (52)(53)(54). Low-level expression of self-specific TCRs may be a general mechanism for protecting against autoimmune diseases.…”

Expansion and Functional Relevance of High-Avidity Myelin-Specific CD4+ T Cells in Multiple Sclerosis

“…Animal data support this hypothesis: Inbred animal strains that develop spontaneous autoimmunity express unique MHC class II alleles that bind peptides with unusually weak affinity, like I-A g7 in nonobese diabetic mice (15), and in analogy, in animals with induced autoimmunity, pathogenic T cells are specific for a peptide that binds poorly to MHC class II, e.g., the encephalitogenic myelin basic protein (MBP) peptide Ac [1][2][3][4][5][6][7][8][9][10][11] to I-A u in B10.PL mice (13,16). In addition, human data indicate that autoreactive peripheral blood CD4 ϩ T cells from patients suffering from organ-specific autoimmunity express TCR that recognize peptide-MHC complexes with low affinity, as measured by dissociation of MHC class II tetramers (17).…”

“…1B, second panel). However, only several myelin epitopes contributed to the increased reactivity observed in MS patients: MBP epitopes (MBP [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] , MBP 111-129 , and MBP 146 -170 ), PLP 139 -154 , and MOG (MOG [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and MOG ) (Fig. 1B).…”

Deficiency of the Src Homology Region 2 Domain-Containing Phosphatase 1 (SHP-1) Causes Enrichment of CD4+CD25+ Regulatory T Cells

“…1). Despite this mode of eliminating autoreactive T cells, every healthy adult still carries potentially harmful self-reactive T cells (2). In the periphery, such autoreactive T cells are rendered inert by mechanisms termed peripheral tolerance (3).…”