T-cell receptor Vbeta deletion and Valpha polymorphism are responsible for the resistance of SWR mouse to arthritis induction

Abstract

Collagen type II-induced arthritis (CIA) develops in susceptible mouse strains after intradermal injections of type II collagen (CII) in complete Freund's adjuvant (CFA). Susceptibility to CIA in mice is linked to genes of the major histocompatibility complex (MHC). Although the SWR mouse has a susceptible MHC haplotype (H2q), it is resistant to CIA. SWR exhibits at least two known immunological defects: (1) it contains a germline deletion of about 50% of T-cell receptor (TCR) Vbeta-chain gene segments, and (2) SWR is deficient in complement component C5. It has been shown that T cells that express TCRValpha11.1 and TCRVbeta8.2 play a substantial role in the pathogenesis of arthritis in the DBA/1 mouse (H2q). We generated SWR transgenic (tg) mice to determine whether the expression of pathogenic Valpha11.1 and/or Vbeta8.2 transgenes would confer arthritis susceptibility. Arthritis was induced in the SWR TCRalphabeta tg mice, but not in SWR TCRbeta tg mice. To address the role of Valpha11.1 in arthritis susceptibility, we examined the allelic polymorphisms of the Tcra-V11-gene subfamily members between the arthritis susceptible DBA/1 mouse and the arthritis-resistant SWR mouse strain. The amino acid sequences of the Valpha11.1 alleles differ at two positions (codons 18 and 68). Accordingly, these two amino acid changes are sufficient to allow the production of pathogenic T cells in SWR mice. This is the first demonstration of the association of a particular Tcra-V allele and arthritis susceptibility in mice.

Induction of experimental autoimmune arthritis by a public epitope of the T cell receptor variable α domain of an arthritogenic T cell clone

“…The T cell-mediated character of this disease was shown by transfer experiments. In support of this hypothesis, two polymorphisms in AV11 were recently suggested to be associated with susceptibility to arthritis in mice [29,30]. The important role of AV11 in collageninduced arthritis was further supported by protection studies using AV11 recombinant protein [28].…”

HLA-DRB1*0402 (DW10) Transgene Protects Collagen- Induced Arthritis-Susceptible H2Aq and DRB1*0401 (DW4) Transgenic Mice from Arthritis

“…Previous studies have shown that V␤8.2 is important in induction of CIA in H2A q mice. Absence of V␤8.2 TCR population in FVB mice is one of the reasons for nonsusceptibility to CIA (40). In vivo depletion of DW10 did not make the transgenic mice susceptible to arthritis suggesting that negative/positive selection of autoreactive cells occur in thymus and is probably influenced by polymorphism in MHC.…”

Immunological Variation Between Inbred Laboratory Mouse Strains

“…SJL/J, FVB/NJ, SWR, C57L, and C57BR strains have germline deletions in the Tcrb-V8 gene, with SJL/J mice having the largest amount of DNA deleted. 7,8,125 TCRB-V8 is expressed on many cell types, including natural killer T (NKT) cells and CD8þNKT cells. 40 NKT cells coexpress TCRB-V8 and the natural killer (NK) cell marker NK1.1 and thus represent a hybrid of the innate and adaptive immune system.…”