Human Th17 subsets

Abstract

Since their discovery as a distinct T helper (Th) cell lineage, Th17 cells have been extensively investigated both in mice and in humans. These studies have identified factors involved in their differentiation and effector functions and have also revealed a high degree of flexibility that seems to be a characteristic of the Th17-cell lineage. In this review, we discuss recent studies addressing the heterogeneity of human Th17 cells, their differentiation requirements, their migratory capacities, and their role in defense against fungi and extracellular bacteria. Keywords: Cytokines r Chemokine receptors r Human r Th17 IntroductionHuman T cells producing IL-17 were described as early as the late 1990s in the context of chronic inflammatory conditions such as rheumatoid arthritis and airway inflammation [1,2], but it was only in 2005 that they were recognized as a new lineage of effector T cells [3]. Three lines of evidence obtained in the mouse system supported this notion. First, pathogenic inflammatory T cells produced high levels of IL-17A, IL-17F, and TNF and were dependent on IL-23 rather than IL-12 for their expansion [3]. Second, naïve CD4 + T cells acquired IL-17-, but not IFN-γ-or IL-4-producing capacity, when activated in vitro in the presence of TGF-β and IL-6 or IL-23 [4][5][6]. Third, overexpression of the orphan nuclear receptor RORγt was sufficient to induce differentiation of Th17 cells, while deficiency of RORγt in T cells attenuated autoimmune disease due to lack of tissue-infiltrating Th17 cells [7]. From these groundbreaking studies, the field has progressed at an astonishing pace, taking advantage of new and powerful technologies that have become accessible in recent years. As in many other areas of immunology, discoveries from studies performed in both experimental animal models and in human systems have contributed to our current understanding of the Th17 system and the role these cells play in physiology and pathology. Here, we will review, in particular, studies that address the heterogeneity of human Th17Correspondence: Dr. Federica Sallusto e-mail: federica.sallusto@irb.usi.ch cells, their differentiation requirements, their migratory capacities, and their role in defense against pathogens. Human Th17: heterogeneity, function, and migrationTo perform their function, effector, and memory T cells have to migrate to specific tissue sites, which are marked by the presence of constitutive or inflammatory chemokines [8]. Several studies have shown that chemokine receptors are differentially expressed on effector and memory T-cell subsets. For example, CCR7 identifies central memory T (T CM ) cells that home to secondary lymphoid organs, and distinguish them from effector memory T (T EM ) cells that home to peripheral nonlymphoid tissues [9]. CXCR3 and CCR5 are preferentially expressed on IFN-γ-producing Th1 cells, while CCR3, CCR4, and CRTH2 are preferentially expressed on subsets of Th2 cells that produce IL-4, . The Th1-and Th2-specifying transcription factors T-bet and GATA3 directly contr...

Mucosal Th17 Cell Function Is Altered during HIV Infection and Is an Independent Predictor of Systemic Immune Activation

“…In the absence of HIV, mucosal Th17 cells produce several cytokines with a range of effector functions (28,38). Because HIV infection is associated with a dramatic reduction in the polyfunctional capacity of HIV-specific CD8 + T cells (39,40), we examined the effector functions of mucosal Th17 cells and their relationship with HIV-associated microbial translocation and immune activation.…”

IL-10: A Paradigm for Counterregulatory Cytokines

“…IL-10 was not only produced by Tr1 cells, but also promoted their differentiation (7). Recently, it also was shown that Staphylococcus aureus priming of naive human T cells generated IL-10-producing Th17 cells (regulatory Th17 cells), potentially as an intrinsic mechanism to suppress excessive inflammation in response to infection (8,9). Studies using in vivo infection with Toxoplasma gondii and Leishmania major revealed that Tbet 1 Th1 cells also secreted IL-10 (10, 11).…”

THE ROLE OF THE DIFFERENT SUBPOPULATIONS OF CD4⁺Т LYMPHOCYTES DURING PREGNANCY

“…Th1 lymphocytes express Tbet transcription factor and receptors CXCR3 [97], CCR6 [106], IL-18R [137] CCR5 [91], and some other (Table 1).…”

“…Th2 lymphocytes express transcription factor Gata3 and receptors CD294 [54], CCR3, CCR4, CCR8, CRTH2, CD62L, CD30 (Table 1) [106]. At that, it should be specified that cytokine division into pro-and antiinflammatory is relative, and often the same cytokines occasionally have both pro-and anti-inflammatory activity, depending on a situation, such as IL-6 and IL-4.…”

“…IL-4, IL-6 [26], transcription repressor Gfi1 [119] participate in inhibition of differentiation in Th1 direction. [7,23], RORγt [106,111], CD26 [11] RORct, IL-23R, IL-12R, [7], CCR2, CXCR3, CCR5, CXCR6, CCR4, CD62L, CCR7, CXCR4, CXCR5 [46] IL-17А, IL-22, IL-21, IL-17F, IL-26 [87,89] Th2 lymphocyte pool is formed mostly in the presence of IL-4, IL-33 and absence of IL-12 [73,102]. IL-1 [110], IL-6 [26] also take part in Th2 differentiation.…”