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Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection
Carly A. Dillen, … , Emanual Maverakis, Lloyd S. Miller
Carly A. Dillen, … , Emanual Maverakis, Lloyd S. Miller
Published February 5, 2018
Citation Information: J Clin Invest. 2018;128(3):1026-1042. https://doi.org/10.1172/JCI96481.
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Research Article Immunology Infectious disease

Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection

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Abstract

The mechanisms that mediate durable protection against Staphylococcus aureus skin reinfections are unclear, as recurrences are common despite high antibody titers and memory T cells. Here, we developed a mouse model of S. aureus skin reinfection to investigate protective memory responses. In contrast with WT mice, IL-1β–deficient mice exhibited poor neutrophil recruitment and bacterial clearance during primary infection that was rescued during secondary S. aureus challenge. The γδ T cells from skin-draining LNs utilized compensatory T cell–intrinsic TLR2/MyD88 signaling to mediate rescue by trafficking and producing TNF and IFN-γ, which restored neutrophil recruitment and promoted bacterial clearance. RNA-sequencing (RNA-seq) of the LNs revealed a clonotypic S. aureus–induced γδ T cell expansion with a complementarity-determining region 3 (CDR3) aa sequence identical to that of invariant Vγ5+ dendritic epidermal T cells. However, this T cell receptor γ (TRG) aa sequence of the dominant CDR3 sequence was generated from multiple gene rearrangements of TRGV5 and TRGV6, indicating clonotypic expansion. TNF- and IFN-γ–producing γδ T cells were also expanded in peripheral blood of IRAK4-deficient humans no longer predisposed to S. aureus skin infections. Thus, clonally expanded γδ T cells represent a mechanism for long-lasting immunity against recurrent S. aureus skin infections.

Authors

Carly A. Dillen, Bret L. Pinsker, Alina I. Marusina, Alexander A. Merleev, Orly N. Farber, Haiyun Liu, Nathan K. Archer, Da B. Lee, Yu Wang, Roger V. Ortines, Steven K. Lee, Mark C. Marchitto, Shuting S. Cai, Alyssa G. Ashbaugh, Larissa S. May, Steven M. Holland, Alexandra F. Freeman, Loren G. Miller, Michael R. Yeaman, Scott I. Simon, Joshua D. Milner, Emanual Maverakis, Lloyd S. Miller

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Figure 1

IL-1β–/– mice are protected against an S. aureus skin reinfection.

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IL-1β–/– mice are protected against an S. aureus skin reinfection.

(A) ...
(A) Time line for S. aureus skin reinfection model. (B) Representative photographs of skin lesions. (C) Mean total lesion size (cm2) ± SEM (n = 10/group). (D) Representative S. aureus in vivo bioluminescent signals. (E) Mean total flux (photons/s) ± SEM (n = 10/group). (F) Ex vivo CFUs from d7 infected skin (n = 5/group). (G–J) Mean total lesion size (cm2) ± SEM and mean total flux (photons/s) ± SEM after 8-week (G and H) or 20-week (I and J) convalescent period (n = 5–10/group). †P < 0.01,; ‡P < 0.001, compared with 1° mice, as calculated by 2-way ANOVA (C, E, G–J) or 2-tailed Student’s t test (F). Results in B–E and G and H are a compilation of 2 independent experiments. Results in F are representative of 2 independent experiments.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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