Abstract
When helper T (TH) cell polarization was initially described three decades ago, the TH cell universe grew dramatically. New subsets were described based on their expression of few specific cytokines. Beyond TH1 and TH2 cells, this led to the coining of various TH17 and regulatory (Treg) cell subsets as well as TH22, TH25, follicular helper (TFH), TH3, TH5 and TH9 cells. High-dimensional single-cell analysis revealed that a categorization of TH cells into a single-cytokine-based nomenclature fails to capture the complexity and diversity of TH cells. Similar to the simple nomenclature used to describe innate lymphoid cells (ILCs), we propose that TH cell polarization should be categorized in terms of the help they provide to phagocytes (type 1), to B cells, eosinophils and mast cells (type 2) and to non-immune tissue cells, including the stroma and epithelium (type 3). Studying TH cells based on their helper function and the cells they help, rather than phenotypic features such as individual analyzed cytokines or transcription factors, better captures TH cell plasticity and conversion as well as the breadth of immune responses in vivo.
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References
Galli, E. et al. The end of omics? High dimensional single cell analysis in precision medicine. Eur. J. Immunol. 49, 212–220 (2019).
Tortola, L. et al. High-dimensional T helper cell profiling reveals a broad diversity of stably committed effector states and uncovers interlineage relationships. Immunity 53, 597–613 (2020).
Parish, C. R. & Liew, F. Y. Immune response to chemically modified flagellin: III. Enhanced cell-mediated immunity during high and low zone antibody tolerance to flagellin. J. Exp. Med. 135, 298–311 (1972).
Bottomly, K., Mathieson, B. J. & Mosier, D. E. Anti-idiotype induced regulation of helper cell function for the response to phosphorylcholine in adult BALB/c mice. J. Exp. Med. 148, 1216–1227 (1978).
Kappler, J. & Marrack, P. The role of H-2-linked genes in helper T-cell function. I. In vitro expression in B cells of immune response genes controlling helper T-cell activity. J. Exp. Med. 146, 1748–1764 (1977).
Tada, T., Takemori, T., Okumura, K., Nonaka, M. & Tokuhisa, T. Two distinct types of helper T cells involved in the secondary antibody response: independent and synergistic effects of Ia− and Ia+ helper T cells. J. Exp. Med. 147, 446–458 (1978).
Mosmann, T. R., Cherwinski, H., Bond, M. W., Giedlin, M. A. & Coffman, R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 2348–2357 (1986).
Szabo, S. J. et al. A novel transcription factor, T-bet, directs TH1 lineage commitment. Cell 100, 655–669 (2000).
Zhang, D. H., Cohn, L., Ray, P., Bottomly, K. & Ray, A. Transcription factor GATA-3 is differentially expressed in murine TH1 and TH2 cells and controls TH2-specific expression of the interleukin-5 gene. J. Biol. Chem. 272, 21597–21603 (1997).
Zheng, W. P. & Flavell, R. A. The transcription factor GATA-3 is necessary and sufficient for TH2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997).
Gershon, R. K. & Kondo, K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 18, 723–737 (1970).
Nishizuka, Y. & Sakakura, T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166, 753–755 (1969).
Chen, Y., Kuchroo, V. K., Inobe, J. I., Hafler, D. A. & Weiner, H. L. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237–1240 (1994).
Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).
Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).
Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).
Becher, B., Durell, B. G. & Noelle, R. J. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J. Clin. Invest. 110, 493–497 (2002).
Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).
Murphy, C. A. et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003).
Aggarwal, S., Ghilardi, N., Xie, M. H., De Sauvage, F. J. & Gurney, A. L. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem. 278, 1910–1914 (2003).
Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).
Harrington, L. E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).
Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).
Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).
Mangan, P. R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).
Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).
Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).
Zwicky, P., Unger, S. & Becher, B. Targeting interleukin-17 in chronic inflammatory disease: a clinical perspective. J. Exp. Med. 217, e20191123 (2020).
Borghi, M. et al. Antifungal TH immunity: growing up in family. Front. Immunol. 5, 506 (2014).
Bacher, P. et al. Human anti-fungal TH17 immunity and pathology rely on cross-reactivity against Candida albicans. Cell 176, 1340–1355 (2019).
Breitfeld, D. et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192, 1545–1551 (2000).
Schaerli, P. et al. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192, 1553–1562 (2000).
Johnston, R. J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006–1010 (2009).
Mitsdoerffer, M. et al. Proinflammatory T helper type 17 cells are effective B-cell helpers. Proc. Natl Acad. Sci. USA 107, 14292–14297 (2010).
Olatunde, A. C., Hale, J. S. & Lamb, T. J. Cytokine-skewed TFH cells: functional consequences for B cell help. Trends Immunol. 42, 536–550 (2021).
Reinhardt, R. L., Liang, H. E. & Locksley, R. M. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat. Immunol. 10, 385–393 (2009).
Crotty, S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).
Dardalhon, V. et al. IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+IL-10+Foxp3− effector T cells. Nat. Immunol. 9, 1347–1355 (2008).
Veldhoen, M. et al. Transforming growth factor-β ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol. 9, 1341–1346 (2008).
Duhen, T., Geiger, R., Jarrossay, D., Lanzavecchia, A. & Sallusto, F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat. Immunol. 10, 857–863 (2009).
Trifari, S., Kaplan, C. D., Tran, E. H., Crellin, N. K. & Spits, H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells. Nat. Immunol. 10, 864–871 (2009).
Eyerich, S. et al. TH22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J. Clin. Invest. 119, 3573–3585 (2009).
Wu, L. et al. A novel IL-25 signaling pathway through STAT5. J. Immunol. 194, 4528–4534 (2015).
Cosmi, L. et al. Identification of a novel subset of human circulating memory CD4+ T cells that produce both IL-17A and IL-4. J. Allergy Clin. Immunol. 125, 222–230 (2010).
Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature 467, 967–971 (2010).
van Hamburg, J. P. & Tas, S. W. Molecular mechanisms underpinning T helper 17 cell heterogeneity and functions in rheumatoid arthritis. J. Autoimmun. 87, 69–81 (2018).
Zhou, L., Chong, M. M. W. & Littman, D. R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).
Locksley, R. M. Nine lives: plasticity among T helper cell subsets. J. Exp. Med. 206, 1643–1646 (2009).
Tsuji, M. et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer’s patches. Science 323, 1488–1492 (2009).
Sujino, T. et al. Tissue adaptation of regulatory and intraepithelial CD4+ T cells controls gut inflammation. Science 352, 1581–1586 (2016).
Rubtsov, Y. P. et al. Stability of the regulatory T cell lineage in vivo. Science 329, 1667–1671 (2010).
Avni, O. et al. TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat. Immunol. 3, 643–651 (2002).
Fields, P. E., Kim, S. T. & Flavell, R. A. Cutting edge: changes in histone acetylation at the IL-4 and IFN-γ loci accompany TH1/TH2 differentiation. J. Immunol. 169, 647–650 (2002).
Mukasa, R. et al. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity 32, 616–627 (2010).
Kunkl, M., Frascolla, S., Amormino, C., Volpe, E. & Tuosto, L. T helper cells: the modulators of inflammation in multiple sclerosis. Cells 9, 482 (2020).
Ando, D. G., Clayton, J., Kono, D., Urban, J. L. & Sercarz, E. E. Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis (EAE) are of the TH-1 lymphokine subtype. Cell. Immunol. 124, 132–143 (1989).
Voskuhl, R. R. et al. T helper 1 (TH1) functional phenotype of human myelin basic protein-specific T lymphocytes. Autoimmunity 15, 137–143 (1993).
Ferber, I. A. et al. Mice with a disrupted IFN-γ gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J. Immunol. 156, 5–7 (1996).
Krakowski, M. & Owens, T. Interferon-γ confers resistance to experimental allergic encephalomyelitis. Eur. J. Immunol. 26, 1641–1646 (1996).
Komiyama, Y. et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177, 566–573 (2006).
Haak, S. et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J. Clin. Invest. 119, 61–69 (2009).
Kebir, H. et al. Human TH17 lymphocytes promote blood–brain barrier disruption and central nervous system inflammation. Nat. Med. 13, 1173–1175 (2007).
Kang, Z. et al. Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 32, 414–425 (2010).
Regen, T. et al. IL-17 controls central nervous system autoimmunity through the intestinal microbiome. Sci. Immunol. 6, eaaz6563 (2021).
Hirota, K. et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat. Immunol. 12, 255–263 (2011).
Komuczki, J. et al. Fate-mapping of GM-CSF expression identifies a discrete subset of inflammation-driving T helper cells regulated by cytokines IL-23 and IL-1β. Immunity 50, 1289–1304 (2019).
McQualter, J. L. et al. Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis. J. Exp. Med. 194, 873–881 (2001).
Ponomarev, E. D. et al. GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis. J. Immunol. 178, 39–48 (2007).
Galli, E. et al. GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis. Nat. Med. 25, 1290–1300 (2019).
Sheng, W., Png, C. W., Reynolds, J. M. & Zhang, Y. T cell-derived GM-CSF, regulation of expression and function. Immunome Res. 11, https://doi.org/10.4172/1745-7580.1000098 (2015).
Herndler-Brandstetter, D. & Flavell, R. A. Producing GM-CSF: a unique T helper subset? Cell Res. 24, 1379–1380 (2014).
Sheng, W. et al. STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation. Cell Res. 24, 1387–1402 (2014).
Noster, R. et al. IL-17 and GM-CSF expression are antagonistically regulated by human T helper cells. Sci. Transl. Med. 6, 241ra80 (2014).
Murphy, E. et al. Reversibility of T helper 1 and 2 populations is lost after long-term stimulation. J. Exp. Med. 183, 901–913 (1996).
Hegazy, A. N. et al. Interferons direct TH2 cell reprogramming to generate a stable GATA-3+T-bet+ cell subset with combined TH2 and TH1 cell functions. Immunity 32, 116–128 (2010).
Lee, Y. K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009).
Becattini, S. et al. Functional heterogeneity of human memory CD4+ T cell clones primed by pathogens or vaccines. Science 347, 400–406 (2015).
O’Shea, J. & Paul, W. E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327, 1098–1102 (2010).
Kiner, E. et al. Gut CD4+ T cell phenotypes are a continuum molded by microbes, not by TH archetypes. Nat. Immunol. 22, 216–228 (2021).
Eberl, G. & Pradeu, T. Towards a general theory of immunity? Trends Immunol. 39, 261–263 (2018).
Pradeu, T., Jaeger, S. & Vivier, E. The speed of change: towards a discontinuity theory of immunity? Nat. Rev. Immunol. 13, 764–769 (2013).
Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).
Annunziato, F., Romagnani, C. & Romagnani, S. The 3 major types of innate and adaptive cell-mediated effector immunity. J. Allergy Clin. Immunol. 135, 626–635 (2015).
Eberl, G. Immunity by equilibrium. Nat. Rev. Immunol. 16, 524–532 (2016).
Spits, H. et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).
Bradley, L. M., Dalton, D. K. & Croft, M. A direct role for IFN-γ in regulation of TH1 cell development. J. Immunol. 157, 1350–1358 (1996).
Kurtjones, E. A., Hamberg, S., Ohara, J., Paul, W. E. & Abbas, A. K. Heterogeneity of helper/inducer T lymphocytes: I. Lymphokine production and lymphokine responsiveness. J. Exp. Med. 166, 1774–1787 (1987).
Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 448–487 (2007).
de Veer, M. J. et al. Functional classification of interferon-stimulated genes identified using microarrays. J. Leukoc. Biol. 69, 912–920 (2001).
Hertzog, P., Forster, S. & Samarajiwa, S. Systems biology of interferon responses. J. Interferon Cytokine Res. 31, 5–11 (2011).
Trost, M. et al. The phagosomal proteome in interferon-γ-activated macrophages. Immunity 30, 143–154 (2009).
Yates, R. M., Hermetter, A., Taylor, G. A. & Russell, D. G. Macrophage activation downregulates the degradative capacity of the phagosome. Traffic 8, 241–250 (2007).
Ahn, H. J. et al. A mechanism underlying synergy between IL-12 and IFN-γ-inducing factor in enhanced production of IFN-γ. J. Immunol. 159, 2125–2131 (1997).
Kovarik, P. et al. Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated protein kinase whereas IFN-γ uses a different signaling pathway. Proc. Natl Acad. Sci. USA 96, 13956–13961 (1999).
Snapper, C. M. et al. Interferon-γ and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science 236, 944–947 (1987).
Tau, G. & Rothman, P. Biologic functions of the IFN-γ receptors. Allergy 54, 1233–1251 (1999).
Croxford, A. L. et al. The cytokine GM-CSF drives the inflammatory signature of CCR2+ monocytes and licenses autoimmunity. Immunity 43, 502–514 (2015).
Darrieutort-Laffite, C. et al. IL-1β and TNFα promote monocyte viability through the induction of GM-CSF expression by rheumatoid arthritis synovial fibroblasts. Mediators Inflamm. 2014, 241840 (2014).
Kobayashi, S. D. Spontaneous neutrophil apoptosis and regulation of cell survival by granulocyte macrophage-colony stimulating factor. J. Leukoc. Biol. 78, 1408–1418 (2005).
Zhan, Y. et al. The inflammatory cytokine, GM-CSF, alters the developmental outcome of murine dendritic cells. Eur. J. Immunol. 42, 2889–2900 (2012).
Barreda, D. R., Hanington, P. C. & Belosevic, M. Regulation of myeloid development and function by colony stimulating factors. Dev. Comp. Immunol. 28, 509–554 (2004).
Sun, L. et al. GM-CSF quantity has a selective effect on granulocytic vs. monocytic myeloid development and function. Front. Immunol. 9, 1922 (2018).
Guthridge, M. A. et al. Growth factor pleiotropy is controlled by a receptor Tyr/Ser motif that acts as a binary switch. EMBO J. 25, 479–485 (2006).
Guthridge, M. A. et al. Mechanism of activation of the GM-CSF, IL-3, and IL-5 family of receptors. Stem Cells 16, 301–313 (1998).
Becher, B., Tugues, S. & Greter, M. GM-CSF: from growth factor to central mediator of tissue inflammation. Immunity 45, 963–973 (2016).
Sanmarco, L. M. et al. Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes. Nature 590, 473–479 (2021).
Wheeler, M. A. et al. MAFG-driven astrocytes promote CNS inflammation. Nature 578, 593–599 (2020).
Mehta, P. et al. Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities. Lancet Respir. Med. 8, 822–830 (2020).
Crotty, S. A brief history of T cell help to B cells. Nat. Rev. Immunol. 15, 185–189 (2015).
Smith, K. M. et al. TH1 and TH2 CD4+ T cells provide help for B cell clonal expansion and antibody synthesis in a similar manner in vivo. J. Immunol. 165, 3136–3144 (2000).
Howard, M. et al. Identification of a T cell-derived B cell growth factor distinct from interleukin 2. J. Exp. Med. 155, 914–923 (1982).
Kopf, M. et al. Immune responses of IL‐4, IL‐5, IL‐6 deficient mice. Immunol. Rev. 148, 45–69 (1995).
Eisenbarth, S. C. et al. CD4+ T cells that help B cells—a proposal for uniform nomenclature. Trends Immunol. 42, 658–669 (2021).
Koyasu, S. & Moro, K. Type 2 innate immune responses and the natural helper cell. Immunology 132, 475–481 (2011).
Shinkai, K., Mohrs, M. & Locksley, R. M. Helper T cells regulate type-2 innate immunity in vivo. Nature 420, 825–829 (2002).
Yang, D. et al. Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2–MyD88 signal pathway in dendritic cells and enhances TH2 immune responses. J. Exp. Med. 205, 79–90 (2008).
Gasteiger, G., Fan, X., Dikiy, S., Lee, S. Y. & Rudensky, A. Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science 350, 981–985 (2015).
Halim, T. Y. F. et al. Group 2 innate lymphoid cells license dendritic cells to potentiate memory TH2 cell responses. Nat. Immunol. 17, 57–64 (2016).
Halim, T. Y. F. et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 40, 425–435 (2014).
Fort, M. M. et al. IL-25 induces IL-4, IL-5, and IL-13 and TH2-associated pathologies in vivo. Immunity 15, 985–995 (2001).
Liu, Y., Shao, Z., Shangguan, G., Bie, Q. & Zhang, B. Biological properties and the role of IL-25 in disease pathogenesis. J. Immunol. Res. 2018, 6519465 (2018).
Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).
Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).
Price, A. E. et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc. Natl Acad. Sci. USA 107, 11489–11494 (2010).
Renauld, J. C., Houssiau, F., Uyttenhove, C., Vink, A. & Van Snick, J. Interleukin-9: a T-cell growth factor with a potential oncogenic activity. Cancer Invest. 11, 635–640 (1993).
Townsend, M. J. et al. IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity 13, 573–583 (2000).
Noelle, R. J. & Nowak, E. C. Cellular sources and immune functions of interleukin-9. Nat. Rev. Immunol. 10, 683–687 (2010).
Conti, H. R. et al. TH17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J. Exp. Med. 206, 299–311 (2009).
O’Connor, W. et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat. Immunol. 10, 603–609 (2009).
Sonnenberg, G. F. et al. Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. J. Exp. Med. 207, 1293–1305 (2010).
Croxford, A. L. et al. IL-6 regulates neutrophil microabscess formation in IL-17A-driven psoriasiform lesions. J. Invest. Dermatol. 134, 728–735 (2014).
Perera, G. K., Di Meglio, P. & Nestle, F. O. Psoriasis. Annu. Rev. Pathol. 7, 385–422 (2012).
Kashem, S. W. et al. Nociceptive sensory fibers drive interleukin-23 production from CD301b+ dermal dendritic cells and drive protective cutaneous immunity. Immunity 43, 515–526 (2015).
Riol-Blanco, L. et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510, 157–161 (2014).
Rankin, L. C. & Artis, D. Beyond host defense: emerging functions of the immune system in regulating complex tissue physiology. Cell 173, 554–567 (2018).
Sparber, F. & Leibundgut-Landmann, S. Interleukin-17 in antifungal immunity. Pathogens 8, 54 (2019).
Plank, M. W. et al. TH22 cells form a distinct TH lineage from TH17 cells in vitro with unique transcriptional properties and Tbet-dependent TH1 plasticity. J. Immunol. 198, 2182–2190 (2017).
Kubick, N. et al. Interleukins and interleukin receptors evolutionary history and origin in relation to CD4+ T cell evolution. Genes 12, 813 (2021).
Acknowledgements
We thank F. Sallusto and S. Sakaguchi for helpful comments on the manuscript. A.S.D. is supported by the Agence Nationale de la Recherche (ANR FoxoTic), the ARSEP foundation (ARSEP R19191BB) and the FRM (R20097BB); M.I. is supported by the European Research Council (ERC) Consolidator Grant 725038, the ERC Proof of Concept Grant 957502, the Italian Association for Cancer Research grants 19891 and 22737, the Italian Ministry of Health grants RF-2018-12365801 and COVID-2020-12371617, the Lombardy Foundation for Biomedical Research grant 2015-0010, the European Molecular Biology Organization Young Investigator Program and funded research agreements from Gilead Sciences, Takis Biotech, Toscana Life Sciences and Asher Bio. F.J.Q. is supported by NS102807, ES02530, ES029136 and AI126880 from the NIH; RG4111A1 from the National Multiple Sclerosis Society; and PA-1604-08459 from the International Progressive MS Alliance. F.G. is supported by the EMBO YIP, a BMRC Central Research Fund (UIBR) award and a Singapore NRF Senior Investigatorship (NRFI2017-02); TK is supported by the Deutsche Forschungsgemeinschaft (SFB1054, TRR128, TRR274, EXC 2145 (ID 390857198)) and the ERC (CoG647215); A.W. is supported by the Deutsche Forschungsgemeinschaft (TRR128, TRR156, CRC1292 and a Reinhard Koselleck prize); B.B. is supported by the Swiss National Science Foundation (733 310030_170320, 1030 310030_188450 and CRSII5_183478 to B.B.), H2020 Projects (826121, 847782) and the ERC (AdG 882424).
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Tuzlak, S., Dejean, A.S., Iannacone, M. et al. Repositioning TH cell polarization from single cytokines to complex help. Nat Immunol 22, 1210–1217 (2021). https://doi.org/10.1038/s41590-021-01009-w
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DOI: https://doi.org/10.1038/s41590-021-01009-w
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