Exacerbation of Collagen-Induced Arthritis by Oligoclonal, IL-17-Producing γδ T Cells

Abstract

Murine γδ T cell subsets, defined by their Vγ chain usage, have been shown in various disease models to have distinct functional roles. In this study, we examined the responses of the two main peripheral γδ T cell subsets, Vγ1+ and Vγ4+ cells, during collagen-induced arthritis (CIA), a mouse model that shares many hallmarks with human rheumatoid arthritis. We found that whereas both subsets increased in number, only the Vγ4+ cells became activated. Surprisingly, these Vγ4+ cells appeared to be Ag selected, based on preferential Vγ4/Vδ4 pairing and very limited TCR junctions. Furthermore, in both the draining lymph node and the joints, the vast majority of the Vγ4/Vδ4+ cells produced IL-17, a cytokine that appears to be key in the development of CIA. In fact, the number of IL-17-producing Vγ4+ γδ T cells in the draining lymph nodes was found to be equivalent to the number of CD4+αβ+ Th-17 cells. When mice were depleted of Vγ4+ cells, clinical disease scores were significantly reduced and the incidence of disease was lowered. A decrease in total IgG and IgG2a anti-collagen Abs was also seen. These results suggest that Vγ4/Vδ4+ γδ T cells exacerbate CIA through their production of IL-17.

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

“…In the collagen‐induced arthritis model, both γδ 17 cells and Th17 cells are found in joints and draining lymph nodes and the majority of the γδ 17 cells are V γ 4 + /V δ 4 + 22, 24. V γ 4 + cell depletion reduces Th17 cell number60 as well as arthritis severity,22 suggesting that the V γ 4 + /V δ 4 + subset aggravates disease by promoting a Th17 cell response.…”

“…V γ 4 + cell depletion reduces Th17 cell number60 as well as arthritis severity,22 suggesting that the V γ 4 + /V δ 4 + subset aggravates disease by promoting a Th17 cell response. Some components of heat‐killed Mycobacterium tuberculosis in complete Freund's adjuvant or inflammatory cytokines induced by the adjuvant are suggested to induce V γ 4 + /V δ 4 + cell expansion 24, 60…”

“…As described, the importance of IL‐17 in the development of rheumatoid arthritis (RA) is suggested in mouse models and γδ 17 cells are accumulated in arthritic joints,7, 20, 22, 24 but the importance of γδ 17 cells in patients with RA is controversial. A recent report shows that V δ 2 + γδ T cells accumulate in the synovium of patients with RA and produce high levels of IL‐17 as well as IFN‐ γ 98.…”

Diversity of γδ T-cell antigens

“…However, other cd TCRs are diverse initially, and later selected during immune responses. 5,6 At the level of lymphocyte populations, the cd TCRs appear to be less evenly distributed than the other adaptive receptors. In mice, where this has been studied in detail, subsets of cd T cells expressing different Vcs become segregated already during ontogeny due to their sequential developmental patterns in the thymus.…”

“…Despite an enormous potential for receptor diversity in CDR3d, 3 clear evidence of peripheral selection of cd T cells 6 and the occasional emergence of cd T-cell clones, 5 most specificities identified so far are not clone-specific. It is not clear whether this is mainly a bias of the investigators-polyclonal responses are more easily spotted-or an intrinsic property of cd T-cell recognition.…”