IL-36 receptor is expressed by human blood and intestinal T lymphocytes and is dose–dependently activated via IL-36β and induces CD4+ lymphocyte proliferation

Abstract

We show that IL-36R is expressed by T (CD4+ and CD8+) and B (CD19+) lymphocytes in human blood and also by CD4+ T lymphocytes in the intestinal lamina propria. IL-36R protein was mostly stored in the cytoplasm of CD4 lymphocytes and B cells, during steady andthe greatest expression of IL-36R mRNA was measured in CD4+ (T helper) lymphocytesIL-36 β, which functions via IL-36R induced rapid and significant (P <0.05) proliferation of CD4+ lymphocytes, within 48h. IL-36R expression was also maintained on the surface of circulating CD4+ lymphocytes which enter the intestinal lamina propria.In conclusion our study is the first to show that (1) all human blood lymphocytes express IL-36R; (2) IL-36R expression is maintained by circulating CD4+ lymphocytes which enter the intestinal lamina propria and (3) IL-36R/IL-36 β induces rapid CD4 lymphocyte proliferation. The possible significance of these results in the context of human disease is discussed.3

Unopposed IL-36 Activity Promotes Clonal CD4+ T-Cell Responses with IL-17A Production in Generalized Pustular Psoriasis

“…Altogether, our data reveal that GPP pathogenesis involves strong antigen-driven Th17 responses that occur in association with certain HLA-class II alleles and may be facilitated by unopposed IL-36 signaling. While IL-36 may cause T-cell activation via dendritic cell maturation (Foster et al, 2014), we confirm that IL-36 signaling may directly promote CD4 þ T-cell responses (Penha et al, 2016;Vigne et al, 2012). In addition to deficiency of interleukine-36-receptor antagonist (DITRA) due to IL36RN mutations (Marrakchi et al, 2011), our data further suggest that insufficiency of IL36RN by reduced IL36RN expression may also disturb the mechanisms counterbalancing IL-36 following innate immune activation in GPP.…”

“…IL-36 signal promotes TCR-driven proliferation of CD4 D T cells in GPP IL36A, IL36B, and IL36G are proinflammatory cytokines with overlapping effects (Carrier et al, 2011;Foster et al, 2014;Johnston et al, 2011;Mahil et al, 2017) and signal through the same receptor, IL36R (Towne et al, 2004). Immunohistologic staining revealed that a majority of lesional CD4 þ T cells expressed IL36R in GPP (Figure 6e), as reported for CD4 þ T cells in blood, gut, and healthy skin (Mahil et al, 2017;Penha et al, 2016;Vigne et al, 2011Vigne et al, , 2012. CD4 þ T cells are responsive to IL36B (Vigne et al, 2011(Vigne et al, , 2012, and IL36B was abundantly expressed in GPP lesions compared to healthy skin (Figure 6e), consistent with former studies (Carrier et al, 2011;Johnston et al, 2017;Liang et al, 2016;Swindell et al, 2013).…”

Regulation and function of interleukin‐36 cytokines

“…These data have been confirmed by another study which also showed that IL‐36R mRNA was undetectable in B lymphocytes and NK cells . In contrast, a recent study showed the presence of IL‐36R in human CD4 + , CD8 + T cells, and in B lymphocytes . Indirect responses to IL‐36 stimulation, in particular IFN‐γ secretion has been found in human T cell/MDC allogeneic co‐cultures .…”

“…31 In contrast, a recent study showed the presence of IL-36R in human CD4 + , CD8 + T cells, and in B lymphocytes. 50 Indirect responses to IL-36 stimulation, in particular IFNγ secretion has been found in human T cell/MDC allogeneic co-cultures. 33 Mouse T cells express IL-36R and respond directly and indirectly to IL-36 stimulation.…”

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

“…Pretreatment of macrophages with IL-36a enhances the ability of these cells to phagocytose and destroy Escherichia coli in vitro, which might explain how IL-36a provides protection against the outcome of sepsis induced by cecal ligation and puncture (91). In addition, the presence of IL-1RL2 on B cells (104) and the ability of IL-1RL2 to activate M2 macrophages (95) have been reported; however, the biological importance of these observations has not been examined.…”