CD45RC Isoform Expression Identifies Functionally Distinct T Cell Subsets Differentially Distributed between Healthy Individuals and AAV Patients

Abstract

In animal models of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), the proportion of CD45RC T cell subsets is important for disease susceptibility. Their human counterparts are, however, functionally ill defined. In this report, we studied their distribution in healthy controls (HC), AAV patients and in Systemic lupus erythematous (SLE) patients as disease controls. We showed that CD45RC expression level on human CD4 and CD8 T cells identifies subsets that are highly variable among individuals. Interestingly, AAV patients exhibit an increased proportion of CD45RClow CD4 T cells as compared to HC and SLE patients. This increase is stable over time and independent of AAV subtype, ANCA specificity, disease duration, or number of relapses. We also analyzed the cytokine profile of purified CD4 and CD8 CD45RC T cell subsets from HC, after stimulation with anti-CD3 and anti-CD28 mAbs. The CD45RC subsets exhibit different cytokine profiles. Type-1 cytokines (IL-2, IFN-γ and TNF-α) were produced by all CD45RC T cell subsets, while the production of IL-17, type-2 (IL-4, IL-5) and regulatory (IL-10) cytokines was restricted to the CD45RClow subset. In conclusion, we have shown that CD45RC expression divides human T cells in functionally distinct subsets that are imbalanced in AAV. Since this imbalance is stable over time and independent of several disease parameters, we hypothesize that this is a pre-existing immune abnormality involved in the etiology of AAV.

Transient antibody targeting of CD45RC induces transplant tolerance and potent antigen-specific regulatory T cells

“…In humans, Saoudi and colleagues described that human CD45RC high and CD45RC low/-T cells were able to secrete Th1 and Th2 cytokines, respectively, similarly to that observed in rats (10). In addition, the same group described a poor prognosis and a higher risk of acute rejection for kidney transplant patients exhibiting more than 54.7% of CD8 + CD45RC…”

“…In humans, a high proportion of CD45RC high CD8 + T cells before transplantation has been correlated with decreased graft survival in kidney transplanted patients (25). The subset of human T cells expressing CD45RC exhibits cytokine profiles after polyclonal stimulation, similarly to rats (10).…”

“…Several isoforms of the CD45 protein are generated by alternative splicing of exons 4-6 encoding extracellular domains A, B, and C, or O in the absence of the 3 exons (i.e., CD45RA, CD45RB, CD45RC, and CD45RO) and conferring differences in size and charge (8,9). Individuals express different levels of CD45 isoforms (10). While the function of CD45 isoforms remains unclear, their differential expression has been associated with T cell activation's level.…”

Pathogenesis of ANCA-Associated Vasculitis

“…The number of Th17 cells reactive to the autoantigen PR3 was found to be increased in patients with GPA in remission [88•, 113]. Furthermore, Ordonez et al found that AAV patients have an expanded CD45RC-positive T helper cell population that is a source of IL-17 [114]. IL-17 acts on endothelial cells, epithelial cells, and antigen-presenting cells, causing release of chemokines that will activate neutrophils, for example IL-8 and CXCL-1 [115].…”

IL-34 is a Treg-specific cytokine and mediates transplant tolerance

“…CD45RC has been shown in rats, mice, and humans to be a marker of both CD4 + and CD8 + Tregs (15)(16)(17)(18)(19)(20). In a rat cardiac allograft model, we have previously shown that blockade of CD40-CD40L interaction by CD40Ig treatment induces longterm allograft survival through the generation of CD8 lo Tregs, which do not inhibit cardiac allograft rejection (18).…”