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Review
. 2022 Sep 15;209(6):1025-1032.
doi: 10.4049/jimmunol.2200345.

CTLs Get SMAD When Pathogens Tell Them Where to Go

Jenny E Suarez-Ramirez  1 , Linda S Cauley  1 , Karthik Chandiran  2
Affiliations
Review

CTLs Get SMAD When Pathogens Tell Them Where to Go

Jenny E Suarez-Ramirez et al. J Immunol. .

Abstract

Vaccines protect against infections by eliciting both Ab and T cell responses. Because the immunity wanes as protective epitopes get modified by accruing mutations, developing strategies for immunization against new variants is a major priority for vaccine development. CTLs eliminate cells that support viral replication and provide protection against new variants by targeting epitopes from internal viral proteins. This form of protection has received limited attention during vaccine development, partly because reliable methods for directing pathogen-specific memory CD8 T cells to vulnerable tissues are currently unavailable. In this review we examine how recent studies expand our knowledge of mechanisms that contribute to the functional diversity of CTLs as they respond to infection. We discuss the role of TGF-β and the SMAD signaling cascade during genetic programming of pathogen-specific CTLs and the pathways that promote formation of a newly identified subset of terminally differentiated memory CD8 T cells that localize in the vasculature.

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Figures

Figure 1:
Figure 1:. Environmental stimuli influence the migratory properties of pathogen-specific CTLs.
Pathogen-specific CTLs can be divided into two groups that (A) use the bloodstream to circulate between different organs, or (B) extravasate to peripheral tissues. (A) CD69+ CTLs enter the circulation during a robust inflammatory response. Terminally-differentiated TEFF and TTM cells express KLRG1 and CX3CR1 after exposure to inflammatory molecules that signal via SMAD4. (B) Naïve CD8 T cells are programmed for localization in peripheral tissues by migratory DCs that activate TGFβ. During the recovery phase of infection, CD69+ TRM cells remain sequestered from the circulation while S1PR5 is downregulated by TGFβ. TEM cells help restore homeostasis by eliminating APCs in reactive lymph nodes, while TCM cells undergo homeostatic proliferation. (C) After secondary infection, the memory compartment is replenished by TSM cells that express Sca1. TCM cells give rise to secondary TEFF and TRM cells that express CD69.
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