Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by dysregulated T and B lymphocytes. Type I interferons (IFN-I) have been shown to play important pathogenic roles in both SLE patients and mouse models of lupus. Recent studies have shown that B cell intrinsic responses to IFN-I are enough to drive B cell differentiation into autoantibody-secreting memory B cells and plasma cells, although lower levels of residual auto-reactive cells remain present. We speculated that IFN-I stimulation of T cells would similarly drive specific T-cell associated lupus phenotypes including the upregulation of T follicular helper cells and Th17, thereby affecting autoantibody production and the development of glomerulonephritis. Using the B6.Nba2 mouse model of lupus, we evaluated disease parameters in T cell specific IFN-I receptor (IFNAR)-deficient mice (cKO). Surprisingly, all measured CD4+ T cell abnormalities and associated intra-splenic cytokine levels (IFNγ, IL-6, IL-10, IL-17, IL-21) were unchanged and thus independent of IFN-I. In contrast B6.Nba2 cKO mice displayed reduced levels of effector CD8+ T cells and increased levels of Foxp3+ CD8+ regulatory T cells, suggesting that IFN-I induced signaling specifically affecting CD8+ T cells. These data suggest a role for both pathogenic and immunosuppressive CD8+ T cells in Nba2-driven autoimmunity, providing a model to further evaluate the role of these cell subsets during lupus-like disease development in vivo.
Highlights
Received: 1 December 2021Systemic lupus erythematosus (SLE) is an autoimmune disorder in which immune cells and self-reactive antibodies drive multiple organ inflammation and damage
We investigated the role of IFN-I on T cells in B6.Nba2 lupus-prone mice, hypothesizing that IFN-I promote lupus-like disease in this model by enhancing pathogenic T cell populations, such as Th1, Th17 and T follicular helper (Tfh) cells, providing cytokines and/or direct help to bolster an autoimmune response
Since it is well established that lupus-like disease in the B6.Nba2 mouse model deSince it is well established that lupus-like disease in the B6.Nba2 mouse model depends pends on functional type I interferon (IFNAR) expression [25], we evaluated the specific on functional type I interferon (IFNAR) expression [25], we evaluated the specific role IFNrole IFN-I stimulation of T cells play in disease using T-cell specific IFNAR conditional
Summary
Received: 1 December 2021Systemic lupus erythematosus (SLE) is an autoimmune disorder in which immune cells and self-reactive antibodies drive multiple organ inflammation and damage. Albeit being a B cell-driven disease, dysregulation within the T cell compartment has been reported in both SLE patients and mouse models of lupus. SLE patients display increased levels of CD4+ Th17 cells, with concomitantly downregulated CD4+ Th1 and FOXP3+. CD4+ Treg cells [1,2] Abnormal cell subsets, such as CD4-CD8- double negative (DN) T cells and CD8+CD28- T cells have been identified in SLE patients and suggested be the main producers of IL-17 and IL-10, respectively [3,4,5]. SLE patients present with increased populations of circulating IL-21-producing T follicular helper (Tfh) cells, essential for germinal center (GC)-driven B cell differentiation and autoantibody production [8,9,10]
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