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Review
. 2021 Jul 1;13(7):a037937.
doi: 10.1101/cshperspect.a037937.

A Regenerative Perspective on Successful and Failed T-Cell Immunity

Affiliations
Review

A Regenerative Perspective on Successful and Failed T-Cell Immunity

Steven L Reiner. Cold Spring Harb Perspect Biol. .

Abstract

Heightened immunity after a primary infection, persistent control of low-level infection, or vanquished immunity from chronic-active infection and cancer are interrelated issues concerning the nature of T-cell regeneration during immunity. For many regenerating tissues and cellular systems, such as epithelia and blood, there are at least three distinguishable stages of development and repair, marked by progressive loss of self-renewal and progressive commitment to differentiation. T cells seem to be no different. Quiescent precursors become activated and yield anabolic, proliferative progenitors while self-renewing the quiescent precursor population. Activated progenitors then yield differentiated cellular descendants alongside the self-renewal of progenitors. Nomenclature reflecting the mutually opposing nature of T-cell self-renewal and T-cell differentiation would help synchronize phenomena such as T-cell memory, protective immunity, and T-cell exhaustion with other regenerative paradigms, as well as offer new strategies to influence the intensity and duration of immunity.

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Figures

Figure 1.
Figure 1.
Classification of T-cell subsets from a regenerative perspective. This hypothetical, three-layered schema is composed of two major cell fates and an unstable intermediate state: precursors, progenitors, and irreversibly differentiated cells. Progressive commitment to differentiation is accompanied by loss of self-renewal and multipotency, resembling epithelial or hematopoietic growth and repair. Activation of quiescent TCF1+ precursor (red) leads to mobilization of rapidly dividing, anabolic TCF1+ progenitors (purple), while simultaneously self-renewing (looped-back arrows) quiescent descendants (central memory). TCF1+ progenitors undergoing further activation directly yield irreversibly committed TCF1 effector blasts (blue, and also anabolic), while simultaneously self-renewing bipotent TCF1+ progenitors. After antigen clearance, activated TCF1+ progenitors can revert from their unstable anabolic state to become quiescent TCF1+ precursors, but TCF1 cells do not dedifferentiate into TCF1+ cells. Anatomically, precursors circulate among secondary lymphoid organs (SLOs), progenitors concentrate in draining lymphoid organs, and differentiated cells (which arise in draining SLOs) are subsequently dispatched to tissue sites. Other TCF1 cells emerging from anabolic effector blasts include postmitotic effector and exhausted cells. TCF1 effector memory and tissue-resident memory cells are hypothesized to arise from progenitors (or effector blasts) and stabilize into more quiescent peripheral cells after antigen clearance. During chronic responses, TCF1+ progenitors maintain production of TCF1 descendants until capacity for TCF1+ self-renewal is lost. PD-1 blockade hypermobilizes TCF1+ progenitors into greater division and production of fresh TCF1 progeny, rather than restoring functionality to preexisting exhausted TCF1 cells (not shown).

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