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 2

OVA-specific CD8+ T cells are present in the vagina after HSV-2 infection and display a bystander-activated phenotype.

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OVA-specific CD8+ T cells are present in the vagina after HSV-2 infectio...
(A) Experimental schematic to generate an OVA-specific memory compartment followed by intravaginal challenge with wild-type (WT) HSV-2. Mice were euthanized on days 1–7 after WT HSV-2 challenge to assess OVA-specific CD8+ T cells in the vaginal tract (VT). (B) Frequency and counts of CD44+ OVA tetramer–specific cells on days 1–7 after HSV-2 challenge in LM-OVA–immunized mice. Dashed lines indicate mean of OVA-specific cells in the VT of LM-OVA–immunized mice prior to HSV-2 challenge. (C) Frequency of granzyme B+ and NKG2D+ population gated on OVA tetramer–positive population. (D and E) Frequency of granzyme B+ and NKG2D+ population gated on OVA tetramer–positive population within draining lymph nodes (dLN; iliac and inguinal), spleen, and VT. Each dot represents an individual mouse, and data are representative of 1–3 experiments with 4–5 mice per group. (F) HSV gB-specific and OVA-specific memory compartments were generated by immunization of Nur77-GFP mice with LM-OVA-gB or LM-OVA followed by intravaginal challenge with WT HSV-2. Mice were euthanized on day 3 after WT HSV-2 challenge to assess Nur77-expressing populations within gB- and OVA-specific CD8+ T cells in the VT. Red bars indicate HSV gB-specific population within LM-OVA-gB–immunized mice, and blue bars indicate OVA-specific population within LM-OVA–immunized mice. Data are representative of 3 experiments, each with 3 mice per group. Error bars represent mean ± SD. Statistical significance was determined by unpaired t test for B, C, and F, and 1-way ANOVA for D and E. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.