Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection
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
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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Research Article Immunology Infectious disease

Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection

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 5

γδ T cells from draining LNs confer protection.

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γδ T cells from draining LNs confer protection. (A) Draining LNs were ha...
(A) Draining LNs were harvested from d28 IL-1β–/– mice, and γδ T cells or other CD3+ T cells were transferred i.v. 1 day prior to S. aureus inoculation of naive IL-1β–/– mice. (B) Total lesion size (cm2) ± SEM and mean total flux (photon/s) ± SEM (n = 10/group). (C) Draining LNs were harvested from d28 IL-1β–/– mice and γδ T cells, CD4+ T cells, or γδ T cells and CD4+ T cells combined were transferred i.v. 1 day prior to S. aureus inoculation of naive IL-1β–/– mice. (D) Total lesion size (cm2) ± SEM and mean total flux (photon/s) ± SEM (n = 5/group). *P < 0.05; †P < 0.01, between the 2 groups (B) or compared with IL-1β–/– mice without cell transfer (1° IL-1β–/–) (D) as measured by 2-way ANOVA. Results in B are a compilation of 2 independent experiments, and results in D are representative of 2 independent experiments.