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Review
. 2021 Jul 1;13(7):a038083.
doi: 10.1101/cshperspect.a038083.

Homeostasis and Durability of T-Cell Memory-The Resting and the Restless T-Cell Memory

Andreas Radbruch  1 , Mairi Anne McGrath  1 , Francesco Siracusa  1   2 , Ute Hoffmann  1 , Özen Sercan-Alp  1   3 , Andreas Hutloff  4 , Koji Tokoyoda  5 , Hyun-Dong Chang  6   7 , Jun Dong  1
Affiliations
Review

Homeostasis and Durability of T-Cell Memory-The Resting and the Restless T-Cell Memory

Andreas Radbruch et al. Cold Spring Harb Perspect Biol. .

Abstract

The molecular basis of the persistence of experienced T lymphocytes, also known as "memory T lymphocytes," is still enigmatic. We are beginning to understand their considerable heterogeneity and topographic compartmentalization into memory T cells circulating through the body and those residing in a particular tissue. In some tissues, like murine spleen, subpopulations of memory T cells proliferating in the absence of antigen (homeostatic proliferation) have been described. Other populations are maintained resting in terms of transcription, mobility, and proliferation in dedicated survival niches organized by stromal cells. The survival of these memory T cells is conditional on being in such a niche, where they can persist for a lifetime. Circulating memory T lymphocytes of distinct immune responses slowly decline in numbers over time. The rules governing their entry into and exit from blood, as well as their lifestyle outside of the blood and their relation to resident memory T cells are poorly understood. Homeostasis of circulating, proliferating, and resting memory T cells is obviously controlled by different rheostats: tissue-exit and tissue-entry signals for circulating and proliferation-inducing signals for proliferating memory T cells. For tissue-resident, resting memory T cells, it is the availability of their survival niche. Apparently, this mechanism (i.e., the link between memory T cell and stromal cell) is so robust that it provides efficient T-cell memory over a lifetime in tissues such as the bone marrow.

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Figures

Figure 1.
Figure 1.
Topography of circulating, proliferating, and resident memory T lymphocytes in steady state. The localization and migration of three memory T (Tm) lymphocyte cell subsets with different lifestyles (i.e., circulating [Tmcirc], proliferating [Tpm], and tissue-resident memory T [Trm] cells) and their presence in epithelial tissues, blood, secondary lymphoid organs, and bone marrow. In the skin and reproductive tract, motile Trm cells have been observed, while in bone marrow they are immobile. CD69 is a key marker that is expressed by Trm cells; however, Trm cells lacking expression of CD69 have also been suggested. (SC) Stromal cell.
Figure 2.
Figure 2.
Dynamics of memory T-cell populations over time. After an immune reaction, precursors of Trm migrate from blood and SLOs to their target tissue guided by chemokines and adhesion molecules as indicated and differentiate into Trm cells. In circulation, numbers of Tmcirc and Tpm cells gradually decline over time, while numbers of Trm cells initially increase and then presumably are maintained at stable levels. Upon antigenic challenge, Trm cells are reactivated by antigen-presenting cells (APCs), scanning them, and form nonconventional immune clusters in their host tissue and proliferate. To what extent reactivated Trm cells enter the circulation and participate in systemic immune responses is not quite clear. (SC) Stromal cell, (DC) dendritic cell.
Figure 3.
Figure 3.
Conventional and unconventional secondary immune reactions. (A) In secondary lymphoid organs like lymph nodes, memory T (Tm) cells are located in interfollicular regions and the subcapsular sinus. Upon reactivation, memory T cells regain a T follicular helper (Tfh) cell phenotype and control classical secondary immune reactions, resulting in the formation and affinity-maturation of antibody-secreting cells. (B) Resting Trm cells of the bone marrow are scattered over the parenchyma individually, each in close contact with a stromal cell (SC). They have to be scanned by antigen-presenting cells to become reactivated, then leave their niches and form immune clusters with the antigen-presenting cells, vigorously proliferating. (C) In the lungs, memory T cells persist in peribronchial clusters, in association with antigen-presenting cells, including B cells. These clusters might provide very fast reactivation of B and T cells in this barrier organ. (D) In the skin and reproductive tract, motile Trm cells have been described. In secondary immune responses, these motile Trm cells become immobile and proliferate.
Figure 4.
Figure 4.
Rheostats controlling the homeostasis of Tmcirc, Tpm, and Trm cells. According to their different lifestyles, different biological rheostats control the homeostasis of Tmcirc, Tpm, and Trm cells. Tissue entry and tissue exit regulates the homeostasis of Tmcirc cells, while for Tpm cells it is the availability of local proliferation-inducing signals. For Trm cells, it is obviously the continued availability of a survival niche as organized by a stromal cell (SC).
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