Th22 cells are expanded in multiple sclerosis and are resistant to IFN‐β

Th1 and Th17 cells have been considered as effectors in mouse EAE and in the human counterpart, MS. Recently, IL‐22, a Th17‐related, proinflammatory cytokine, has been associated with a new Th cell subset, defined as Th22, involved in chronic inflammatory conditions, such as psoriasis; the role of IL‐22 in MS has not yet been elucidated. Here, we report that similar to Th17 cells, the number of Th22 cells increased in the PB and the CSF of RR MS patients, especially during the active phases of the disease. However, as opposed to Th17 cells, the expansion of Th22 cells occurred before the active phases of the disease. Th22 cells were found to be specific for the autoantigen MBP and also expressed high levels of CCR6 and T‐bet, as for Th17 cells, indicating that Th22 self‐reactive cells could have CNS‐homing properties and be pathogenic in active RRMS patients. Conversely to Th17 cells, Th22 cells displayed lower levels of IFNAR1 and were insensitive to IFN‐β inhibition. These data suggest that expansion of Th22 cells in MS could be one of the factors that critically influence resistance to IFN‐β therapy.

[1]  B. Engelhardt,et al.  C-C chemokine receptor 6–regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE , 2009, Nature Immunology.

[2]  H. Spits,et al.  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 , 2009, Nature Immunology.

[3]  L. Cosmi,et al.  Human interleukin 17–producing cells originate from a CD161+CD4+ T cell precursor , 2008, The Journal of experimental medicine.

[4]  L. Cosmi,et al.  CD161 is a marker of all human IL‐17‐producing T‐cell subsets and is induced by RORC , 2010, European journal of immunology.

[5]  Youjin Lee,et al.  The many faces of Th17 cells. , 2011, Current opinion in immunology.

[6]  E. Tolosa,et al.  Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. , 2009, Brain : a journal of neurology.

[7]  A. Compston,et al.  Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis , 2001, Annals of neurology.

[8]  B. Becher,et al.  IL-22 Is Expressed by Th17 Cells in an IL-23-Dependent Fashion, but Not Required for the Development of Autoimmune Encephalomyelitis1 , 2007, The Journal of Immunology.

[9]  R. Flavell,et al.  Recent advances in IL-22 biology. , 2011, International immunology.

[10]  M. Kaplan,et al.  IL-23 Promotes Maintenance but Not Commitment to the Th17 Lineage1 , 2008, The Journal of Immunology.

[11]  S. Nakae,et al.  IL-17 Plays an Important Role in the Development of Experimental Autoimmune Encephalomyelitis1 , 2006, The Journal of Immunology.

[12]  P. Duquette,et al.  Preferential recruitment of interferon‐γ–expressing TH17 cells in multiple sclerosis , 2009, Annals of neurology.

[13]  S. Durham,et al.  Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. , 2009, The Journal of clinical investigation.

[14]  D. Jarrossay,et al.  Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells , 2009, Nature Immunology.

[15]  J. Saurat,et al.  Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells , 2010, European journal of immunology.

[16]  J. Buer,et al.  The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins , 2008, Nature.

[17]  Nathalie Arbour,et al.  Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation , 2007, Nature Medicine.

[18]  G. Cheng,et al.  The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. , 2008, The Journal of clinical investigation.

[19]  R. Kastelein,et al.  Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain , 2003, Nature.

[20]  Lawrence Steinman,et al.  T helper type 1 and 17 cells determine efficacy of interferon-β in multiple sclerosis and experimental encephalomyelitis , 2010, Nature Medicine.

[21]  G. Schreiber,et al.  The receptor of the type I interferon family. , 2007, Current topics in microbiology and immunology.

[22]  B. Becher,et al.  T(H)17 cytokines in autoimmune neuro-inflammation. , 2011, Current opinion in immunology.

[23]  M. Sospedra,et al.  Immunology of Multiple Sclerosis , 2016, Seminars in Neurology.

[24]  Y. Li,et al.  Increased memory Th17 cells in patients with neuromyelitis optica and multiple sclerosis , 2011, Journal of Neuroimmunology.

[25]  S. Dhib-jalbut,et al.  Serum interferon β-1a (Avonex) levels following intramuscular injection in relapsing-remitting MS patients , 1998, Neurology.

[26]  Yuhong Yang,et al.  T-bet is essential for encephalitogenicity of both Th1 and Th17 cells , 2009, The Journal of experimental medicine.

[27]  J. Kurtzke.  Rating neurologic impairment in multiple sclerosis , 1983, Neurology.

[28]  A. Blauvelt,et al.  Circulating Th17, Th22, and Th1 cells are increased in psoriasis. , 2010, The Journal of investigative dermatology.

[29]  Hergen Spits,et al.  IL‐22‐producing CD4+ T cells: Middle‐men between the immune system and its environment , 2010, European journal of immunology.

[30]  Laura Conti,et al.  T‐helper 17 cells expand in multiple sclerosis and are inhibited by interferon‐β , 2009, Annals of neurology.

[31]  A. Kermode,et al.  IL-22 secreting CD4+ T cells in the patients with neuromyelitis optica and multiple sclerosis , 2013, Journal of Neuroimmunology.

[32]  X. Montalban,et al.  Defining the response to interferon‐β in relapsing‐remitting multiple sclerosis patients , 2006, Annals of neurology.

[33]  Antonio Uccelli,et al.  Th17 Cells in Multiple Sclerosis Express Higher Levels of JAK2, Which Increases Their Surface Expression of IFN-γR2 , 2012, The Journal of Immunology.

[34]  C. Walline,et al.  IL-7Rα confers susceptibility to experimental autoimmune encephalomyelitis , 2011, Genes and Immunity.

[35]  V. Kuchroo,et al.  New pieces in the puzzle: How does interferon‐β really work in multiple sclerosis? , 2009, Annals of neurology.

[36]  T. Mcclanahan,et al.  IL-23 drives a pathogenic T cell population that induces autoimmune inflammation , 2005, The Journal of experimental medicine.

[37]  K. Asadullah,et al.  IL‐22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis , 2006, European journal of immunology.

[38]  Jianping Jin,et al.  IFN-β Inhibits Human Th17 Cell Differentiation1 , 2009, The Journal of Immunology.

[39]  A. Cavani,et al.  IL-17 and IL-22: siblings, not twins. , 2010, Trends in immunology.