Local Foxp3+ Treg cells maintain lineage integrity of commensal specific immunity in the skin

A dynamic dialogue between host and microbiota ensures that commensal colonization occurs as a state of mutualism, the breakdown of which is associated with chronic inflammatory disorders. We recently demonstrated that distinct commensal species drive unique cutaneous immune responses, which are key to tissue homeostasis. However, the regulatory mechanisms ensuring host/microbial mutualism and prevention of tissue pathology are not understood. We sought to determine the role of Foxp3+ T regulatory (Treg) cells in this setting and developed a mouse model whereby Foxp3+ Treg cell function is selectively perturbed within skin tissue. Colonization by commensal bacteria (S. epidermidis) drove recruitment of skin resident IL-17A-producing CD8+ tissue resident memory-like T cells, crucially in the absence of overt inflammation. However, mice with impaired local regulation also exhibited recruitment of IL-13-producing CD8+ T cell populations, which was not evident in control mice. Strikingly, production of type 2 cytokines (including IL-13) by CD8+ T cells is rarely described, except in patients with severe cutaneous inflammation, including atopic dermatitis. Importantly, these findings demonstrate a key role for Foxp3+ Treg cells in maintaining appropriate immune responses upon colonization with cutaneous commensal bacteria. Investigating the cellular mechanisms underlying generation of this  IL-13+ CD8+ T cell population will aid our understanding of how to target and treat chronic inflammatory skin disorders in the future.

Selected publications:

Fonseca DM, Hand TW, Han SJ, Gerner MY, Glatman Zaretsky A, Byrd AL, Harrison OJ, Ortiz AM, Quinones M, Trinchieri G, Brenchley JM, Brodsky IE, Germain RN, Randolph GJ, Belkaid Y. Microbiota-Dependent Sequelae of Acute Infection Compromise Tissue-Specific Immunity. Cell. 2015 Oct 8;163(2):354-66

Naik S, Bouladoux N, Linehan JL, Han SJ, Harrison OJ, Wilhelm C, Conlan S, Himmelfarb S, Byrd AL, Deming C, Quinones M, Brenchley JM, Kong HH, Tussiwand R, Murphy KM, Merad M, Segre JA, Belkaid Y. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature. Nature. 2015 Apr 2;520(7545):104-8.

Schiering C, Krausgruber T, Chomka A, Fröhlich A, Adelmann K, Wohlfert EA, Pott J, Griseri T, Bollrath J, Hegazy AN, Harrison OJ, Owens BM, Löhning M, Belkaid Y, Fallon PG, Powrie F. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature. 2014 Sep 25;513(7519):564-8.

Brain O, Owens BM, Pichulik T, Allan P, Khatamzas E, Leslie A, Steevels T, Sharma S, Mayer A, Catuneanu AM, Morton V, Sun MY, Jewell D, Coccia M, Harrison O, Maloy K, Schönefeldt S, Bornschein S, Liston A, Simmons A. The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release. Immunity. 2013 Sep 19;39(3):521-36. 

Kirchberger S, Royston DJ, Boulard O, Thornton E, Franchini F, Szabady RL, Harrison O, Powrie F. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J Exp Med. 2013 May 6;210(5):917-31.

Coccia M, Harrison OJ, Schiering C, Asquith MJ, Becher B, Powrie F, Maloy KJ. IL-1b mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4(+) Th17 cells. J Exp Med. 2012 Aug 27;209(9):1595-609.

Harrison OJ, Maloy KJ. Innate immune activation in intestinal homeostasis. J Innate Immun. 2011;3(6):585-93.

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