Review articleStem cell-like memory T cells: A perspective from the dark side
Introduction
The ‘non-self’ is distinguished from the ‘self’ by the immune system and subsequently eradicated to keep individual homeostasis. Immune memory is a critical mechanism for accelerating the elimination of certain pathogens or danger signals and sustaining homeostasis after the primary immune response. The establishment of an immune memory state allows immune cells to survive for a long time after antigenic stimulation, recognize familiar antigens continuously and produce more rapid and powerful secondary immunity. The memory cells carrying the most suitable antigen recognition markers exist persistently, acting as a physiological barrier for vertebrates to protect themselves from microorganism’s infection and tumors. Heterogenous TM cells can be classified into TSCM cells, central memory T (TCM) cells and effector memory T (TEM) cells according to phenotypic molecules such as CD45RO, CD62L and CCR7 (discussed further in the following sections). TSCM cells are identified as the least differentiated and long-lived TM cell population with a strong capacity for self-renewal and a multipotent differentiation into other subsets of memory cells [1]. Recent studies have demonstrated that TSCM cells for therapeutic application will benefit human B-cell malignancies, melanoma and gastric cancer [2], [3], [4], [5]. However, TSCM cells with complex biological signals can drive and sustain multiple diseases, such as autoimmune diseases, adult T cell leukemia (ATL), human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) infections. Due to the similarity of virus infections and space limitations, we mainly focus on autoimmunity and HIV-1 in the following sections.
Autoimmune diseases are a group of chronic disorders characterized by the production of increased amounts of proinflammatory cytokines and sustained aberrant autoimmune responses. Currently, the prevalence and incidence of systemic lupus erythematosus (SLE) [6], [7], [8], multiple sclerosis (MS) [9], [10], [11] and type 1 diabetes (T1D) [12], [13] have increased significantly in populations worldwide. Patients with autoimmune diseases are susceptible to other autoimmune diseases and more likely to suffer from fatigue, causing severe emotional damage and job restrictions [14], [15], [16]. The treatment of autoimmune diseases still highly depends on immunosuppressants and biological agents. However, immunosuppressive agents have serious side effects, and biologics are expensive and mainly applied for patients with high disease activity [17]. In clinical practice, the anti-inflammation and immunosuppressive therapy often failed and the autoimmune diseases relapse easily, which could be due to immune memory persistence in autoimmune diseases. Hence, the crucial role of TM cells in driving the persistent progression of several autoimmune diseases has received extensive attention in recent years [18], [19], [20]. A better understanding of the complex molecular mechanisms involved in the induction and functional regulations of long-lived TM cells in autoimmunity is critical for the establishment and development of novel immunotherapeutic strategies.
In contrast to excessive immune responses of autoimmune diseases, HIV-1, which causes acquired immunodeficiency syndrome (AIDS), destroys the human immune system by attacking CD4+ lymphocytes. Thirty-eight million people are living with HIV globally according to UNAIDS in 2019. Most people aged 15–49 years died of preventable HIV-related diseases such as pulmonary tuberculosis and cryptococcal infection [21]. Antiretroviral treatment (ART) can limit the replication of HIV-1 but cannot eliminate the latent provirus in resting cellular reservoirs. As a result, patients will rebound after interrupting treatment due to financial constraints. CD4+ resident memory T (TRM) cells in the cervical mucosa have been reported to preferentially support latent HIV-1 infection and maintain persistent viral reservoir due to the expression of IL-7 receptor-α (CD127) on this subpopulation [22], [23]. Improved understanding of the functional role of TM cells, especially self-renewing TM cells, should lead to novel immunotherapies for eliminating or permanently suppress the activity of HIV-1.
Section snippets
The discovery, differentiation and amplification of TSCM cells
A group of postmitotic CD44loCD62LhiCD8+ T cells, which was first defined as TSCM cells, was discovered by Zhang in 2005 in mouse models of human graft-versus-host disease (GVHD) [24]. The human counterpart of total TSCM cells was identified six years later, only accounting for 2–3% of all circulating T cells [1]. The mRNA sequence analysis has indicated that TSCM cells possess a unique gene expression profile, which resembles traditional TM cells even more [1]. Another subsequent research
The renewal and cell memory
TSCM cells represent the least differentiated and long-lived T cell memory subset [1], [44]. This discrete memory subset is an independent cell stage with unique phenotypes and functions between TN and TCM subsets [25], [45]. Antigen-specific TSCM cells preferentially survive among memory cells after antigen elimination. They stably persist for the long term in a state of perpetual flux throughout the human lifespan [46]. Vaccine-induced CD8+ TSCM cells, specific to yellow fever antigens, were
Wnt/β-catenin/TCF-1 signaling and memory formation
It has been shown that the Wnt/β-catenin signature is involved in the generation of CD4+ TSCM cells or long-lived CD8+ TM cells and secondary immune responses [55], [56]. The canonical Wnt signaling pathway is initiated by binding one of the 19 different Wnt ligands to a Frizzled (FRZ) receptor such as LDL receptor-related protein 5 (LRP5) or LRP6. Activated Wnt signaling allows β-catenin to accumulate in the cytoplasm through arresting the phosphorylation and degradation of β-catenin by
TSCM cells exacerbate autoimmune diseases
Antigen-specific TSCM cells were discovered to participate in immune responses against various antigens, including viruses [86], bacteria [87], parasites [88] and tumor-associated antigens [89]. TSCM cells provide long-term protective immunity for antitumor immunity, most likely based on reactivity to self-antigens [90]. Thus, as by-products of antitumor, autoimmunity mediated by TM cells is unavoidable. A fraction of TSCM cells can recognize autoantigenic peptides to break immunological
HIV-1 in CD4+ TSCM cells
The frequency of CD8+ TSCM cells was declined in the patients with chronic, untreated HIV-1 infection and restored by ART [115], [116], [117]. A high-level of CD8+ TSCM cells improved the prognosis in patients with HIV. In contrast with CD8+ TSCM, CD4+ TSCM cells can preserve the virus in a quiescent latent state for a long time, although ART effectively inhibits the replication of HIV-1. After HIV-1 infection, the CD4+ TSCM population will be damaged with the contraction of CD4+ T cells, but
The potential of therapeutic strategies targeting TSCM cells
Different strategies have been explored to expand TSCM cells in vitro for tumor therapy because they can proliferate and survive vigorously under the continuous stimulation of tumor antigen. In contrast, blocking the signal transduction of TSCM cells to attenuate their generation, maintenance and effector function is a promising treatment for autoimmune diseases and HIV chronic infection. Due to the distinct etiologies and immune state, there are some differences in the therapeutic strategies
Conclusion
TSCM cells possess the properties of self-renewal and multi-differentiation and the ability to perform effector functions. Given that TSCM-driven diseases are often characterized by chronic inflammation, whether mediated by a viral infection or high autoimmune response, treatment strategies are consistently biased towards blocking the persistence of the diseases and preventing recurrence. It is critical to analyze transcriptome profiles and effector-like molecules of TSCM cells and explore the
CRediT authorship contribution statement
Shujun Gao: Conceptualization, Investigation, Writing-original draft, Visualization. Xiuting Liang: Investigation, Visualization. Hui Wang: Investigation, Visualization. Boyang Bao: Investigation. Keyu Zhang: Investigation. Yanling Zhu: Conceptualization, Funding acquisition. Qixiang Shao: Conceptualization, Funding acquisition, Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The present study was supported by grants from National Natural Science Foundation of China (grant nos. 81671541, 81273202, 81701545 and 82071738), Clinical Medicine Science & Technology Project of Jiangsu Province of China (grant no. BL2013024), Primary Research & Development Plan (Social Development) of Xuzhou City (KC19147), National College Students’ innovation and entrepreneurship training program (201910299341X, 202010299073Z). We also would like to thank Yangjing Zhao for reading the
References (152)
- et al.
The changing demographic pattern of multiple sclerosis epidemiology
Lancet Neurol.
(2010) - et al.
Reckoning with mortality: global health, HIV, and the politics of data
Lancet
(2020) - et al.
Transcriptional profiles reveal a stepwise developmental program of memory CD8(+) T cell differentiation
Vaccine
(2015) - et al.
Modulation of mTOR Signalling Triggers the Formation of Stem Cell-like Memory T Cells
EBioMedicine
(2016) - et al.
IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors
Blood
(2013) - et al.
Suppressors of cytokine signaling (SOCS) in T cell differentiation, maturation, and function
Trends Immunol.
(2009) - et al.
Polarization diversity of human CD4+ stem cell memory T cells
Clin. Immunol.
(2015) - et al.
Human Stem Cell-like Memory T Cells Are Maintained in a State of Dynamic Flux
Cell Rep.
(2016) - et al.
Homeostatic Cytokines Drive Epigenetic Reprogramming of Activated T Cells into a “Naive-Memory” Phenotype
iScience
(2020) - et al.
Differentiation and persistence of memory CD8(+) T cells depend on T cell factor 1
Immunity
(2010)
Suppression of Tcf1 by Inflammatory Cytokines Facilitates Effector CD8 T Cell Differentiation
Cell Rep.
CD8(+) T Lymphocyte Self-Renewal during Effector Cell Determination
Cell Rep.
AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival
Cell Metab.
AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo
Cell Metab.
IL-7-Induced Glycerol Transport and TAG Synthesis Promotes Memory CD8+ T Cell Longevity
Cell
Cytometry by time-of-flight shows combinatorial cytokine expression and virus-specific cell niches within a continuum of CD8+ T cell phenotypes
Immunity
CD161(int)CD8+ T cells: a novel population of highly functional, memory CD8+ T cells enriched within the gut
Mucosal Immunol.
A human memory T cell subset with stem cell–like properties
Nat. Med.
Modulation of CD8(+) memory stem T cell activity and glycogen synthase kinase 3beta inhibition enhances anti-tumoral immunity in gastric cancer
Oncoimmunology
Harnessing Stem Cell-Like Memory T Cells for Adoptive Cell Transfer Therapy of
Cancer
A primary care back pain screening tool: Identifying patient subgroups for initial treatment
Arthritis Rheum.
The effect of ethnicity and genetic ancestry on the epidemiology, clinical features and outcome of systemic lupus erythematosus
Rheumatology (Oxford)
Global, regional, and national burden of multiple sclerosis 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016
Lancet Neurol.
The changing epidemiology of type 1 diabetes: why is it going through the roof?
Diabetes Metab. Res. Rev.
The increasing onset of type 1 diabetes in children
J. Pediatr.
Vitamin D in SLE: a role in pathogenesis and fatigue? A review of the literature
Lupus
Fatigue Sleep, and Autoimmune and Related Disorders
Front Immunol.
Systemic lupus erythematosus and lupus nephritis
Nat. Rev. Drug Discov.
Tissue Resident CD8 Memory T Cell Responses in Cancer and Autoimmunity
Front. Immunol.
Brain-resident memory T cells generated early in life predispose to autoimmune disease in mice
Sci. Transl. Med.
Resident memory T cells are a cellular reservoir for HIV in the cervical mucosa
Nat. Commun.
Host-reactive CD8+ memory stem cells in graft-versus-host disease
Nat. Med.
Superior T memory stem cell persistence supports long-lived T cell memory
J. Clin. Invest
Paths to stemness: building the ultimate antitumour T cell
Nat. Rev. Cancer
Transcriptional control of effector and memory CD8+ T cell differentiation
Nat. Rev. Immunol.
Transcriptional and Epigenetic Regulation of Effector and Memory CD8 T Cell Differentiation
Front. Immunol.
Distinct regulation of effector and memory T-cell differentiation
Immunol. Cell Biol.
Progressive contraction of the latent HIV reservoir around a core of less-differentiated CD4(+) memory T Cells
Nat. Commun.
Memory Stem T Cells in Autoimmune Disease: High Frequency of Circulating CD8+ Memory Stem Cells in Acquired Aplastic Anemia
J. Immunol.
PD-1 expression on human CD8 T cells depends on both state of differentiation and activation status
AIDS
T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?
Nat. Rev. Immunol.
Identification, isolation and in vitro expansion of human and nonhuman primate T stem cell memory cells
Nat. Protoc.
Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells
Nat. Med.
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