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Review
. 2018 Jul 31:9:1751.
doi: 10.3389/fimmu.2018.01751. eCollection 2018.

Genealogy, Dendritic Cell Priming, and Differentiation of Tissue-Resident Memory CD8+ T Cells

Michel Enamorado  1 , Sofía C Khouili  1 , Salvador Iborra  2 , David Sancho  1
Affiliations
Review

Genealogy, Dendritic Cell Priming, and Differentiation of Tissue-Resident Memory CD8+ T Cells

Michel Enamorado et al. Front Immunol. .

Abstract

Tissue-resident memory CD8+ T (Trm) cells define a distinct non-recirculating subset. Trm cells constitute a first line of defense against local infections in barrier tissues, but they are also found in non-barrier tissues and play a role in antitumor immunity. Their differentiation in tissues and their phenotypical, transcriptional, and functional characteristics are the object of active research. Herein, we will discuss the potential existence of committed CD8+ Trm precursors and the genealogy of memory CD8+ T cell subsets. In addition to the priming of naive T cells, there is some plasticity of antigen-experienced effector and memory T cell subsets to generate Trm precursors. Local inflammation, antigen presentation, and cytokines drive Trm differentiation. It is of prime interest how specific dendritic cell subsets modulate priming and differentiation of Trm cells, as well as their reactivation within tissues. Research on how we can manipulate generation of memory T cells subsets is key for improved vaccination strategies.

Keywords: circulating memory; dendritic cells; differentiation; infection; memory CD8+ T cell; plasticity; priming; tissue-resident memory.

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Figures

Figure 1
Figure 1
Possible models that explain the generation of a committed Trm precursor in secondary lymphoid organs. (A) One cell, one fate model. Distinct naive T cells will exhibit a different lineage decision determined by the quality (intensity of signal) of their TCR. (B) One cell, multiple fates model. B.1., Asymmetric cell division in T lymphocytes may determine fate diversification. B.2., Signal strength model. The strength of the signals 1, 2, and 3 determines the fate of the activated CD8+ T cells, with low strength signals generating central memory T (Tcm) precursors and high strength supporting the generation of terminal differentiated effectors. B.3., Decreasing potential model. This model proposes that a short duration of antigenic stimulation favors development of activated cells that will give rise to greater numbers of Tcm cells, while longer duration of stimulation promotes terminal effector cell differentiation and death.
Figure 2
Figure 2
Genealogy of Trm. (A) During primary infection, immunization, or other insults, naive T lymphocytes differentiate into precursors of circulating memory cells, effectors, and putative precursors of Trm (pre-Trm) cells that can differentiate into Trm cells in the skin, in response to viruses (VACV/HSV) or tumors. (B,C) Inflammation in the intestine (B) or in the upper respiratory tract (C) is able to promote Trm generation. (D) In the female reproductive tract, proliferating pre-existing Trm cells contribute substantially to the boosted secondary Trm population and can exit non-lymphoid tissues to convert into new Trm cells in lymphoid tissues. (E) Under steady-state conditions, circulating memory T cells can differentiate into Trm cells in the lung of mice previously infected with influenza A virus. (F) Circulating memory [effector memory T (Tem) or central memory T (Tcm)] cells can differentiate into Trm cells in the skin upon secondary challenge with viruses or tumors.
Figure 3
Figure 3
Differential role of antigen-presenting cells in priming, expansion/differentiation, and reactivation of tissue-resident memory T cells. (A) In mice, optimal generation of Trm in response to VACV or Flu requires CD8+ T cells cross-priming by DNGR-1+ dendritic cells (cDC1, CD8α+, and CD103+), while circulating memory T cells could be primed by both CD11bhi (cDC2) or cDC1. Naive T cells cross-primed by cDC1 receive CD24 co-stimulation, IL-15 and IL-12 specifically produced by this dendritic cell (DC) subset, contributing to the generation of committed Trm precursors. (B) Monocytes (Ly6C+) and monocyte-derived DC (Mo-DCs) contribute to expansion of Trm in response to HSV or Yersinia by secretion of inflammatory cytokines, and also modulate the generation/differentiation of specific Trm subpopulations (CXCR3hiCX3CR1lo; CD69+CD103−). In addition, reactivation of Trm cells in response to HSV-2, requires MHC-I expression in CD301b+ DC. (C) Notably, human CD1c+, but not CD141+, induce CD103 expression on CD8+ T cells and their accumulation in the lung, in a process dependent on TGF-β1.
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