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Review
. 2022 Aug 17:13:907172.
doi: 10.3389/fimmu.2022.907172. eCollection 2022.

Stem-like T cells and niches: Implications in human health and disease

Linglu Yi  1 , Li Yang  1
Affiliations
Review

Stem-like T cells and niches: Implications in human health and disease

Linglu Yi et al. Front Immunol. .

Abstract

Recently, accumulating evidence has elucidated the important role of T cells with stem-like characteristics in long-term maintenance of T cell responses and better patient outcomes after immunotherapy. The fate of TSL cells has been correlated with many physiological and pathological human processes. In this review, we described present advances demonstrating that stem-like T (TSL) cells are central players in human health and disease. We interpreted the evolutionary characteristics, mechanism and functions of TSL cells. Moreover, we discuss the import role of distinct niches and how they affect the stemness of TSL cells. Furthermore, we also outlined currently available strategies to generate TSL cells and associated affecting factors. Moreover, we summarized implication of TSL cells in therapies in two areas: stemness enhancement for vaccines, ICB, and adoptive T cell therapies, and stemness disruption for autoimmune disorders.

Keywords: adoptive cell therapies; autoimmune disorders; immune checkpoint blockade; niches; stem-like T cells.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
T cell stemness: milestones and key discoveries in the last 12 years (, –31). TM, T memory cells; TSCM, T memory stem cells; HTLV-1, human T cell lymphotropic virus type 1; CAR, chimeric antigen receptor; LCMV, lymphocytic choriomeningitis virus; TDLN, tumor-draining lymph node.
Figure 2
Figure 2
Developmental trajectory of CD8+ T cells toward effector (TEFF) and exhausted (TEX) CD8+ T cells in response to different antigen stimulation conditions. Stem-like T cells emerge during the T cell differentiation. (A) When antigen clear and stimuli cease, activated T cells differentiate into memory stem cell-like T cells (TSCM), central memory (TCM) T cells or effector memory (TEM) T cells in terms of signal strength (51). (B) Induced by TOX-based epigenetic regulation, TSCM cells become stem-like progenitor exhausted T cells co-expressed TCF1, PD1, TOX and CXCR5. These stem-like exhausted T cells then become TCF1-PD1+TOX+CX3CR1+ transitory exhausted T (TTRANS) cells, which give rise to terminally exhausted (TEX) T cells (–56).
Figure 3
Figure 3
Representative niches supporting the maintenance of stem-like CD8+ T cells. (A) Stem-like CD8+ T cells in lymphoid niches differentiate into cytotoxic effector T cells, regulating tumor regression (44). (B) CCR7+ naïve CD8+ T cells localize and in the inner cortex (blue) and depend on homeostatic factors from niche supported by fibroblastic reticular cell. Activation process of CD8+ T cells can be divided into three phases, during which regulation signals are unleashed from surrounding, especially DCs (–125). (C) After activation signals, T cells undergo symmetric or asymmetric cell division. Daughter cells transform into TEFF or memory T cells depending on their distance to DCs (32, 126). (D) Tumors with high dense of TILs show APC-niches, containing cDC1, cDC2 and helper CD4 T cells and stem-like CD8 T cells (, –130). (E) Comparisons of human and mouse cDCs found in TDLNs and tumors (, , , , –134). cDC, conventinal dendritic cell; TDLN, tumor-draining lymph node (, , –140).
Figure 4
Figure 4
Signaling pathways and epigenetics regulating self-renewal of T lymphocytes (, , , –181). WNT-β-catenin and transducer and activator of transcription 3 (STAT3) signals are mainly involved for the self-renewal regulation. Additionally, a crucial role is played by chromatin modifiers, which can add repressive histone marks to genes responsible for maintaining stemness, or catalyze DNA methylation on genes regulating differentiation.
Figure 5
Figure 5
Strategies that might be utilized to generate stem-like T cells. (A) Progress of T cells differentiation toward effector T (TEFF) cell pool depends on the strength of stimulatory signals. Differentiating progress of primed TN cells can be delayed or suppressed by targeted inhibitors (such as mTOR, GSK3β, MEK, AKT inhibitor); or by using cytokines, such as interleukin‐21 (IL-21), interleukin-7 (IL-7), interleukin-15 (IL-15), or by using proper costimulatory signal; or by taming metabolic modulators; or by curtailing TCR signaling (, , , –204). (B) Direct reprogramming methods using naïve- or stem-associated factors or miRNAs (205, 206). (C) A two-step induction method is shown. By enforcing expression of OCT4, SOX2, KLF4 and MYC, terminal TEFF cells can be programmed into iPS cells, which are then re-differentiated into TN cells by inducing NOTCH signals (–214). GSK3β, glycogen synthase 3β; TN, naïve T; TEFF, TCM, effector T; iPS, induced pluripotent stem; OCT4, octamer-binding transcription factor 4; SOX2, sex determining region Y BOX 2; KLF4, Kruppel-like factor 4.
Figure 6
Figure 6
Schematic representation of clinical stem cell memory T (TSCM) cells product and programming process (, , 243). Naïve T (TN) cells were then stimulated to transform to TSCM cells with IL-15, IL-21 and IL-7. To maximize the induction of TSCM, GSK-3β inhibitor can be used in addition to the above cytokines. TSCM cells can be also isolated directly from PBMCs by a set of markers. Representative programming methods include introducing exogenous genes like specific CAR, TCR and suicide genes, or directly editing endogenous genes. Requirements of GMP grade for main procedures are indicated in the figure. PBMC, peripheral blood mononuclear cells, CAR, chimeric antigen receptor, TCR, T cell receptor; GMP, good manufacturing practice.
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