ACQUIRED RESISTANCE AGAINST PENETRATION BY STRONGYLODIES RATTI IS MEDIATED BY IL-33-DEPENDENT INDUCTION OF GAMMA DELTA T CELLS

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Degree type
PhD
Graduate group
Immunology
Discipline
Immunology and Infectious Disease
Subject
Cutaneous Immunity
gamma delta T cell
Helminth infection
Inteleukin-33
myeloid cells
Skin barrier
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01/01/2025
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Jean, Erin, Evonne
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Abstract

Interleukin 33 (IL-33) is an alarmin cytokine released from damaged epithelia essential for protecting against soil-transmitted gastrointestinal helminth (STH) infection. However, whether IL-33 serves any role in cutaneous immunity against parasites remains unclear. While epithelial cells are considered the predominant source of IL-33, our recent work demonstrates that CD11c+ myeloid antigen-presenting cells (APCs) can express IL-33 to shape Type 2 immunity. We developed a percutaneous infection model using Strongylodies ratti, a rodent-specific STH, to better understand the mechanisms of acquired host protection and the potential role of IL-33. Data show that C57BL/6 mice develop resistance to percutaneous penetration and distinct phenotypic characteristics of type 2 immunity upon secondary challenge, but IL-33 deficient mice lack resistance to penetration. Surprisingly, mice with a selective IL-33 deficiency only in myeloid APCs (CD11cCre) also failed to develop secondary resistance to S. ratti, suggesting that myeloid-derived IL-33 is essential for resistance to percutaneous infection. Mechanistically, we find that loss of myeloid IL-33 impairs the recruitment of gd T cells that express the IL-33 receptor ST2 and CD62L+ gd T cells. Additionally, mice that lack all gd T cells show defective protective immunity against S. ratti. Interestingly, mice lacking the Type 2 transcription factor STAT6 (Signal transducer and activator of transcription 6) have no defects in primary or secondary cutaneous immunity suggesting that IL-33 drives non-canonical protective immune responses in the skin mediated by gd T cells. These investigations imply that myeloid APCs are a necessary source of IL-33 that drives acquired immunity against helminths, potentially through regulating unique CD62L+/ST2+ populations of gd T cells and potentially their effector function(s).

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Herbert, De'Broski
Date of degree
2025
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