Memory T cells possess an innate-like function in local protection from mucosal infection
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
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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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 7

Human memory CD8+ T cells in the vaginal tissue acquire bystander phenotype upon cytokine treatment.

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Human memory CD8+ T cells in the vaginal tissue acquire bystander phenot...
Cells from vaginal tissues obtained from prolapse repair surgeries were cultured in vitro for 24 hours with varying combinations of IFN-α/β (1,000 U) and IL-12/15/18 (100 ng/mL). (A) Left: Representative flow plot shows the distribution of CD8+ T cells based on CD45RA and CCR7 markers highlighting memory (blue) and naive (gray) compartments. Right: Graph plot shows coexpression of granzyme B and IFN-γ within each compartment after treatment with medium or cytokines. Each dot represents an individual condition, and the color code for each condition is the same as in B. (B) Staggered histogram separated per different cytokine treatments showing IFN-γ and granzyme B expression within the memory CD8+ T cell compartment. (C) Human PBMCs were cultured for 24 hours with IFN-α/β (1,000 U) alone or with IL-12/15/18 (100 ng/mL). Graph plots show memory CD8+ T cells expressing granzyme B and IFN-γ with varying cytokine combinations. (D) Flow plot shows the distribution of CD8+ T cells as naive (CCR7+CD45RA+), TEM (CCR7–CD45RA–), and TEMRA (CCR7–CD45RA+). Graph plot represents each CD8+ T cell subset within an individual donor followed by expression of granzyme B and IFN-γ within each subset. Each dot represents an individual donor, and data are pooled from 5 separate donors. Error bars represent mean ± SD. Statistical significance was determined by 1-way ANOVA with Tukey’s multiple comparisons. *P < 0.05, ****P < 0.0001.