IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4+ T cells

Abstract

IntroductionThe interleukin-1 (IL-1) family of cytokines comprises 11 members, including IL-1␣, IL-1␤, IL-18, IL-33, and the recently renamed IL-36␣, ␤, ␥ (previously known as IL-1F6, IL-1F8, and IL-1F9). 1 All these cytokines use heterodimeric receptors for signaling. IL-1, IL-33, and IL-36 bind to specific receptor ␣-chains, which are IL-1RI for IL-1␣ and IL-1␤, T1/ST2 (also known as IL-33R) for IL-33, and IL-36R (previously termed IL-1Rrp2) for IL-36, and then recruit the same coreceptor IL-1R accessory protein (IL-1RAcP). IL-18 uses IL-18R␣ and the coreceptor IL-18R␤. On receptor binding, all IL-1 family cytokines activate similar intracellular signals, including NF-B and mitogenactivated protein kinase (MAPK) pathways. IL-1 receptor antagonist (IL-1Ra) and IL-36Ra (previously termed IL-1F5), 2 additional members of the IL-1 family, act as natural inhibitors for the biologic activities of IL-1 and IL-36, respectively. [2][3][4] IL-1␣, IL-1␤, IL-18, and IL-33 are produced by activated innate immune cells (neutrophils, monocytes, macrophages, and dendritic cells) and epithelial cells, and stimulate proinflammatory innate and adaptive immune responses. More specifically, these cytokines influence CD4 ϩ T-cell responses and their polarization into the different T helper (Th) subsets Th1, Th2, and Th17. IL-1 promotes the proliferation and survival of naive CD4 ϩ T cells and plays a critical role in Th17 differentiation. 5-9 IL-18 and IL-33 stimulate the polarization of CD4 ϩ T cells into Th1 and Th2, respectively,10 although the selectivity of these responses may be modulated by the cytokine environment. Consistently, Th1, Th2, and Th17 cells selectively express the IL-1 family cytokine receptors IL-18R␣, T1/ST2, and IL-1RI, respectively. 10 IL-36 cytokines and IL-36R are abundantly expressed by keratinocytes and other epithelial cell types. 4,[11][12][13] IL-36 plays a major role in mouse experimental skin inflammation and in human psoriasis both in the initiation and regulation of inflammatory responses. [14][15][16][17][18][19] Furthermore, the association of a form of generalized pustular psoriasis with genetic IL-36Ra deficiency in humans argues in favor of a significant role of IL-36 in inflammatory skin diseases. 20,21 Recently, we have shown that dendritic cells (DCs) express IL-36R and that IL-36 stimulates the production of several cytokines and enhances the expression of costimulatory molecules in bone marrow-derived DCs (BMDCs). The stimulatory effects of IL-36 were more robust than those of the other members of the IL-1 family. In addition, IL-36 stimulated the production of interferon ␥ (IFN-␥), IL-4, and to a lesser extent IL-17 by cultured splenocytes and activated CD4 ϩ T cells, and IL-36 was able to act as an adjuvant to stimulate Th1 responses in vivo. 22 In the results described herein we show that, among CD4 ϩ T-cell subsets, IL-36R is predominantly expressed by naive CD4 ϩ T (referred to also as naive Th) cells and that IL-36 stimulates activated naive CD4 ϩ T (referred to also as Th0) cell ...

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

“…The study therefore shows differences in the expression of IL-36R between humans and mice. In mice IL-36R has been reported to be expressed by splenic CD4+ T lymphocytes but not by CD8+ T lymphocytes or B lymphocytes [2]. Our study also differs from that of Foster et al, [14] which reports a lack of expression of IL-36R in human lymphocytes.…”

“…There is now mounting evidence, from murine studies, that the IL-36R/IL-36α axis may have an important role in skin disorders [1][2][3]. This could also be the case in humans since missense mutations within IL-36RN genes, which encode for IL-36RA, an IL-36R antagonist, have been shown to be associated with pustular psoriasis [4].…”

“…The expression of IL-36R by immune cells and the effect of IL-36 α-γ on these cells may also be important in the aetiology of many other inflammatory pathologies [reviewed 6]. Murine studies have shown that IL-36R is expressed on naive CD4+ Th cells and that low concentration of IL-36 α-γ (100 ng/ml) directly induces proliferation of these cells [2]. In patients with psoriatic arthritis, both IL-36R and IL-36α expression is increased in the synovial lining and also in infiltrating CD 138+ plasma cells [7].…”

The Role of Cytokines of Interleukin 36 Family in Immunopathogenesis of Psoriasis

“…Активируя факторы транскрипции, они способствуют повышению секреции иммунными клетками провоспалитель-ных цитокинов [47]. Рецептор IL-36R обнаружен на поверхности кератиноцитов, ДК и наивных Т-лимфоцитов (Th0) [48,49]. Антагонист рецеп-тора IL-36ra блокирует активацию сигнальных путей, в результате чего сигнал с поверхности клетки не проводится на ядро [46].…”

IL-36–Induced Toxicity in Neonatal Mice Involves TNF-α Production by Liver Myeloid Cells

“…IL-36a, IL-36b, and IL-36g can stimulate the production of different cytokines by both human and mouse dendritic cells (DCs) (21,22). IL-36b can induce proliferation and IL-2 secretion in naive mouse T cells (Th0), and synergizes with IL-12 to stimulate Th1 responses (23). The administration of IL-36b to adult (AD) mice immunized against methylated BSA (mBSA) led to enhanced IFN-g production by draining lymph node cells exposed to mBSA ex vivo and enhanced anti-mBSA Ab levels in vivo (22).…”