Trichinella spiralis Infection Mitigates Collagen-Induced Arthritis via Programmed Death 1-Mediated Immunomodulation

Abstract

Helminth infection induces Th2-biased immune responses and inhibitory/regulatory pathways that minimize excessive inflammation to facilitate the chronic infection of helminth in the host and in the meantime, prevent host hypersensitivity from autoimmune or atopic diseases. However, the detailed molecular mechanisms behind modulation on inflammatory diseases are yet to be clarified. Programmed death 1 (PD-1) is one of the important inhibitory receptors involved in the balance of host immune responses during chronic infection. Here, we used the murine model to examine the role of PD-1 in CD4+ T cells in the effects of Trichinella spiralis infection on collagen-induced arthritis (CIA). Mice infected with T. spiralis demonstrated higher expression of PD-1 in the spleen CD4+ T cells than those without infection. Mice infected with T. spiralis 2 weeks prior to being immunized with type II collagen displayed lower arthritis incidence and significantly attenuated pathology of CIA compared with those of uninfected mice. The therapeutic effect of T. spiralis infection on CIA was reversed by blocking PD-1 with anti-PD-1 antibody, associated with enhanced Th1/Th17 pro-inflammatory responses and reduced Th2 responses. The role of PD-1 in regulating CD4+ T cell differentiation and proliferation during T. spiralis infection was further examined in PD-1 knockout (PD-1−/−) C57BL/6 J mice. Interestingly, T. spiralis-induced alteration of attenuated Th1 and enhanced Th2/regulatory T cell differentiation in wild-type (WT) mice was effectively diminished in PD-1−/− mice characterized by recovered Th1 cytokine levels, reduced levels of Th2 and regulatory cytokines and CD4+CD25+Foxp3+ cells. Moreover, T. spiralis-induced CD4+ T cell proliferation suppression in WT mice was partially restored in PD-1−/− mice. This study introduces the first evidence that PD-1 plays a critical role in helminth infection-attenuated CIA in a mouse model by regulating the CD4+ T cell function, which may provide the new insights into the mechanisms of helminth-induced immunomodulation of host autoimmunity.

Th2 signals are not essential for the anti‐arthritic effects of Trichinella spiralis in mice

“…Presumably due to the higher burden of muscle larvae, the mortality was higher (Figure B) and IgG reduction was more remarkable (Figure ) in STAT6KO mice than in WT mice. Cheng et al reported that Ts reduced whole IgG and IgG2a levels, but did not affect the IgG1 level . This is in contrast to our result that Ts reduced both IgG1 and IgG2a levels.…”

“…Regarding other helminths, Th2 signals were reported to be essential for the anti‐arthritic effects . Recently, Cheng et al reported that Ts infection prevented CIA. Then, here we examined Th2‐dependency of the anti‐arthritic effects of Ts and demonstrated that Ts suppressed CIA in the genetic absence of STAT6 (Figure A,B).…”

“…37 Regarding other helminths, Th2 signals were reported to be essential for the anti-arthritic effects. [6][7][8] Recently, Cheng et al 38 reported…”

GdX/UBL4A‐knockout mice resist collagen‐induced arthritis by balancing the population of T h 1/T h 17 and regulatory T cells

“…Splenocytes from wild-type (WT) and GdX-KO mice were suspended in Roswell Park Memorial Institute 1640 medium containing 10% newborn calf serum, 100 units/ml penicillin, and 100 units/ml streptomycin at 5 3 10 6 cells/ml in the presence or absence of denatured chick CII (50 mg/ml) for 72 h (10,11,23). For intracellular cytokine staining, splenocytes were stimulated with a cell activation cocktail with Brefeldin A (BioLegend) for 6 h, then the cells were stained with specific fluorescence antibodies as described in the figure legends.…”

“…Previous studies showed that IL-17 plays an important role in the generation of inflammatory pain (8,9). Overexpression of IL-17 exacerbates arthritis (10), whereas neutralization of IL-17 with an antibody effectively ameliorates RA (11). Clinical trials indicated that antibodies against IL-17 reduced synovial inflammation and prevented joint destruction in arthritis (12,13).…”