Redundancy in Antigen-Presenting Function of the HLA-DR and -DQ Molecules in the Multiple Sclerosis-Associated HLA-DR2 Haplotype

Abstract

The three HLA class II alleles of the DR2 haplotype, DRB1*1501, DRB5*0101, and DQB1*0602, are in strong linkage disequilibrium and confer most of the genetic risk to multiple sclerosis. Functional redundancy in Ag presentation by these class II molecules would allow recognition by a single TCR of identical peptides with the different restriction elements, facilitating T cell activation and providing one explanation how a disease-associated HLA haplotype could be linked to a CD4+ T cell-mediated autoimmune disease. Using combinatorial peptide libraries and B cell lines expressing single HLA-DR/DQ molecules, we show that two of five in vivo-expanded and likely disease-relevant, cross-reactive cerebrospinal fluid-infiltrating T cell clones use multiple disease-associated HLA class II molecules as restriction elements. One of these T cell clones recognizes >30 identical foreign and human peptides using all DR and DQ molecules of the multiple sclerosis-associated DR2 haplotype. A T cell signaling machinery tuned for efficient responses to weak ligands together with structural features of the TCR-HLA/peptide complex result in this promiscuous HLA class II restriction.

Degenerate TCR recognition and dual DR2 restriction of autoreactive T cells: Implications for the initiation of the autoimmune response in multiple sclerosis

“…5). In addition to DR2 0 s ability to preferentially present a pool of stimulatory antigens, a dual DR2 (DR2a and DR2b) restriction may provide an additional mechanism for the DR2-associated increased risk for MS. Our results are consistent with recent reports [20,21] on the restriction of PHA-and MBP-reactive TCC by multiple DR and DQ molecules. TCR deg T cells' pathogenic role is supported by their secretion of pro-inflammatory cytokines and the cross-reactivity against myelin antigens (Fig.…”

TCR Bias and HLA Cross-Restriction Are Strategies of Human Brain-Infiltrating JC Virus-Specific CD4+ T Cells during Viral Infection

“…However, in addition to mounting a more efficient immune response against infectious organisms, crossrestriction may increase the risk for autoimmunity. A putative physiological role of cross-restriction in facilitating T cell activation was supported by our previous observation using TCCs that were in vivo clonally expanded in the cerebrospinal fluid of an MS patient during relapse, which allowed us to demonstrate a correlation between the stimulatory potential of peptides and their ability to be presented by different restriction elements (52).…”

“…Peptide VP1 34 (amino acid sequence VDSITEVECFLTPEM) contains four negatively charged in the side-chain conformation of N57a (single letter code for amino acid is used), two important replacements, DRA1*01:01 A61a replaced by DQA1*01:02 R61a and DRA1*01:01 A68a replaced by DQA1*01:02 H68a, resulted in the introduction of two positive charges at TCR-contacting positions in DQA1*01:02. With respect to the b-chains, four potential TCR-contacting residues are identical among the DRB1*15:01, DRB5*01:01, and DQB1*06:02 molecules, and two replacements in DQB1*06:02 resulted in conserved charge or minor change (52). The side chains of all these amino acids in the VP1 34 -DQA1*01:02/ DQB1*06:02 complex most likely confer a particular topography to this complex responsible for TCR bias.…”

“…The weak recognition of self-peptide-self-HLA complexes during positive selection in the thymus is a prerequisite for the development of T cells that are able to recognize foreign peptide-self-HLA complexes and implies that the T cell repertoire contains cross-reactive T cells that are in principle autoreactive and able to induce autoimmune diseases such as MS (57). Some examples of myelin basic protein-specific T cell clones (TCCs) as well as data from in vivo clonally expanded cerebrospinal fluid-infiltrating T cells from MS patients that are able to recognize different peptides in the context of different HLA class II molecules have been reported (52)(53)(54). However, cross-reactivity (i.e., the ability to recognize multiple peptides) and HLA cross-restriction (the ability to use multiple restriction elements to recognize the same and/or different peptides) do not seem to be features exclusively found in autoreactive T cells, as it has been reported that TCCs specific to foreign pathogens such as HSV type 2 (55), influenza A virus (56), and Mycobacterium tuberculosis (51) are also able to recognize different peptides in the context of different restriction elements.…”

“…However, some examples of human T cells that are able to recognize different peptides in the context of one or several restriction elements have been described by us and others (51)(52)(53)(54)(55)(56). The weak recognition of self-peptide-self-HLA complexes during positive selection in the thymus is a prerequisite for the development of T cells that are able to recognize foreign peptide-self-HLA complexes and implies that the T cell repertoire contains cross-reactive T cells that are in principle autoreactive and able to induce autoimmune diseases such as MS (57).…”