Memory T cells possess an innate-like function in local protection from mucosal infection
Tanvi Arkatkar, … , Martin Prlic, Jennifer M. Lund
Tanvi Arkatkar, … , Martin Prlic, Jennifer M. Lund
Published March 23, 2023
Citation Information: J Clin Invest. 2023;133(10):e162800. https://doi.org/10.1172/JCI162800.
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Research Article Immunology Infectious disease

Memory T cells possess an innate-like function in local protection from mucosal infection

Abstract

Mucosal infections pose a significant global health burden. Antigen-specific tissue-resident T cells are critical to maintaining barrier immunity. Previous studies in the context of systemic infection suggest that memory CD8+ T cells may also provide innate-like protection against antigenically unrelated pathogens independent of T cell receptor engagement. Whether bystander T cell activation is also an important defense mechanism in the mucosa is poorly understood. Here, we investigated whether innate-like memory CD8+ T cells could protect against a model mucosal virus infection, herpes simplex virus 2 (HSV-2). We found that immunization with an irrelevant antigen delayed disease progression from lethal HSV-2 challenge, suggesting that memory CD8+ T cells may mediate protection despite the lack of antigen specificity. Upon HSV-2 infection, we observed an early infiltration, rather than substantial local proliferation, of antigen-nonspecific CD8+ T cells, which became bystander-activated only within the infected mucosal tissue. Critically, we show that bystander-activated CD8+ T cells are sufficient to reduce early viral burden after HSV-2 infection. Finally, local cytokine cues within the tissue microenvironment after infection were sufficient for bystander activation of mucosal tissue memory CD8+ T cells from mice and humans. Altogether, our findings suggest that local bystander activation of CD8+ memory T cells contributes a fast and effective innate-like response to infection in mucosal tissue.

Authors

Tanvi Arkatkar, Veronica Davé, Irene Cruz Talavera, Jessica B. Graham, Jessica L. Swarts, Sean M. Hughes, Timothy A. Bell, Pablo Hock, Joe Farrington, Ginger D. Shaw, Anna Kirby, Michael Fialkow, Meei-Li Huang, Keith R. Jerome, Martin T. Ferris, Florian Hladik, Joshua T. Schiffer, Martin Prlic, Jennifer M. Lund

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Figure 6

Memory CD8+ T cells acquire a bystander phenotype upon cytokine exposure.

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Memory CD8+ T cells acquire a bystander phenotype upon cytokine exposure...
(A) Splenocytes from C57BL/6 (gray dots) and Collaborative Cross (CC-RIX) mice (white dots) were cultured in vitro for 24 hours with IFN-α/β (1,000 U) alone or with IL-12/15/18 (100 ng/mL). Granzyme B and IFN-γ expression was assessed within activated memory CD8+ T cells (CD44+) gated by flow cytometry. (B) Vaginal cells and splenic cells from LM-OVA memory mice were cultured in vitro for 24 hours with IFN-α/β (1,000 U) and IL-12/15/18 (100 ng/mL). IFN-γ and granzyme B expression within naive (CD44–) and memory CD8+ T (CD44+) cell populations was measured. Each dot represents an individual mouse, and data are representative of at least 2 experiments with 4–10 mice per mouse strain. Error bars represent mean ± SD. Statistical significance was determined by 1-way ANOVA with Tukey’s multiple comparisons (A) or unpaired t test (B). **P < 0.01, ****P < 0.0001.