TIM-4 Has Dual Function in the Induction and Effector Phases of Murine Arthritis

Abstract

T cell Ig and mucin domain (TIM)-4 is involved in immune regulation. However, the pathological function of TIM-4 has not been understood and remains to be clarified in various disease models. In this study, DBA/1 mice were treated with anti–TIM-4 mAb during the induction or effector phase of collagen-induced arthritis (CIA). Anti–TIM-4 treatment in the induction phase exacerbated the development of CIA. In vitro experiments suggest that CD4 T cells bind to TIM-4 on APCs, which induces inhibitory effect to CD4 T cells. In contrast, therapeutic treatment with anti–TIM-4 mAb just before or after the onset or even at later stage of CIA significantly suppressed the development and progression by reducing proinflammatory cytokines in the ankle joints without affecting T or B cell responses. Consistently, clinical arthritis scores of collagen Ab-induced arthritis, which is not mediated by T or B cells, were significantly reduced in anti–TIM-4–treated mice with a concomitant decrease of proinflammatory cytokines in the joints. In vitro, macrophages secreted proinflammatory cytokines in response to TIM-4-Ig protein and LPS, which were reduced by the anti–TIM-4 mAb. The anti–TIM-4 mAb also inhibited the differentiation and bone-resorbing activity of osteoclasts. These results indicate that TIM-4 has two distinct functions depending on the stage of arthritis. The therapeutic effect of anti–TIM-4 mAb on arthritis is mediated by the inhibition of proinflammatory cytokine production by inflammatory cells, osteoclast differentiation, and bone resorption, suggesting that TIM-4 might be an appropriate target for the therapeutic treatment of arthritis.

Fragile TIM-4–expressing tissue resident macrophages are migratory and immunoregulatory

“…It was previously proposed that therapeutic anti-TIM-4 treatment inhibits CD4 + T cells that express a TIM-4 ligand and that anti-TIM-4 could reduce proinflammatory cytokine secretion in bone marrow-derived macrophages (BMDMs) (49); however, the authors did not assess Ly6C -CD169 + tissue-resident macrophages, which differ considerably from BMDMs developmentally and functionally. Additionally, as we submitted this paper, an anti-TIM-4 mAb that does not discriminate between donor and recipient TIM-4 was shown to promote prolonged Treg-dependent skin allograft survival (41) by skewing Teff generation and promoting Tregs in response to CD11c + Flt3L-induced DCs.…”

Blockade of Tim-1 and Tim-4 Enhances Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice

“…23 Blockade of Tim-4 with RMT4-53 exacerbates the induction phase of collagen-induced arthritis by enhanced T cell proliferation and increased IFNγ and IL-17 secretion. 31 Furthermore, Albacker et al showed that Tim-4 blockade (21H12) reversed the induction of intranasal tolerance, resulting in increased proliferative and cytokine responses (IL-4, IFNγ) of T cells. 32 In addition, reduced CD4 T cell responses in Tim-4 Tg mice lead to reduced airway hyper-responsiveness in a murine model of asthma.…”

Tim-4 in Health and Disease: Friend or Foe?

“…However, in collagen-induced arthritis (CIA), Tim-4 displayed dual function in the induction and effector phases. In the induction phase, anti-Tim-4 mAb exacerbated the development of CIA, while the arthritis scores and proinflammatory cytokines were reduced in anti-Tim-4 treated mice at effector phase (6). In the induction of experimental autoimmune encephalomyelitis (EAE) model, anti-Tim-4 treatment greatly ameliorated the clinical feature of EAE (7).…”

“…Unlike other Tim molecules, Tim-4 is mainly expressed on antigen-presenting cells (APCs) but not on T cells (5). In addition, Tim-4, identified as a natural ligand of Tim-1, can modulate T cell proliferation, which is involved in the development of multiple immune diseases (6,7).…”