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 4

Adoptively transferred bystander-activated CD8+ T cells delay the progression of lethal HSV-2 infection and lower the viral burden.

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Adoptively transferred bystander-activated CD8+ T cells delay the progre...
(A) Experimental outline to compare the viral burden of mice receiving CD8+ T cells stimulated with medium or cytokines (IL-12/15/18 plus IFN-α/β) after WT HSV-2 challenge. CD8+ T cells were purified from splenocytes and draining lymph nodes and were derived from CD45.1 donor mice. The cells were stimulated with medium (RP10) or cytokines (10 ng/mL IL-12/15/18 plus 1,000 U IFN-α/β; activated) for 5 hours and washed before intravenous injection into CD45.2 recipient mice. (B) Representative flow plots showing intracellular granzyme B staining in medium- and cytokine-treated memory CD8+ T cells at 5 hours. IFN-γ levels were measured by ELISA from supernatants obtained after 5 hours of incubation. (C and D) Mice were monitored for clinical score and survival after the lethal HSV-2 challenge. (E) Vaginal washes were obtained after HSV-2 infection, and viral titers were measured by RT-PCR on days 1 and 6 after HSV-2 infection. (F) Mice were euthanized on days 1–3 after WT HSV-2 challenge and adoptive transfer to assess frequency and counts of donor CD45.1+ CD8+ T cells in the VT. Percent frequency of granzyme B+ population was gated on CD45.1+ CD8+ T cells. Data are pooled from at least 3 independent experiments with n = 5–10 for the control and experimental groups. Error bars represent mean ± SEM. Statistical significance was determined by 2-way ANOVA with Tukey’s multiple comparisons and by unpaired t test (E and F). *P < 0.05.