T memory stem cells in health and disease

Abstract

T memory stem (T_SCM) cells are a rare subset of memory lymphocytes endowed with the stem cell-like ability to self-renew and the multipotent capacity to reconstitute the entire spectrum of memory and effector T cell subsets. Cumulative evidence in mice, nonhuman primates and humans indicates that T_SCM cells are minimally differentiated cells at the apex of the hierarchical system of memory T lymphocytes. Here we describe emerging findings demonstrating that T_SCM cells, owing to their extreme longevity and robust potential for immune reconstitution, are central players in many physiological and pathological human processes. We also discuss how T_SCM cell stemness could be leveraged therapeutically to enhance the efficacy of vaccines and adoptive T cell therapies for cancer and infectious diseases or, conversely, how it could be disrupted to treat T_SCM cell driven and sustained diseases, such as autoimmunity, adult T cell leukemia and HIV-1.

Figure 1:. Hierarchical model of human T-cell differentiation.

Following antigen priming, naïve T cells (T_N) progressively differentiate into diverse memory T-cell subpopulations and ultimately into terminally differentiated effector T cells (T_TE). T-cell subsets are distinguished by the combinatorial expression of the indicated surface markers. As T_N progressively differentiate into T_TE, they lose or acquire specific functional and metabolic attributes. T_SCM, T memory stem cell; T_CM, central memory T cell; T_EM, effector memory T cell; ΔΨm, mitochondrial membrane potential.

Figure 2:. T_SCM-based therapeutic interventions for human diseases.

T memory stem cells (T_SCM) can be either tamed (left panel) to treat T_SCM-driven diseases such as autoimmunity, T-cell leukemia and T-cell tropic infections or exploited (right panel) to potentiate T cell-based immunotherapies against cancer and infectious diseases. Left panel: WNT antagonists or short hairpin RNA (shRNA) targeting key molecules involved in WNT signaling such as T cell factor 7 (TCF7) could be used to disrupt long-lasting, self-renewing T_SCM reservoirs by driving them to differentiate into short-lived subsets such as effector memory T cells (T_EM). Nanoparticle or aptamer technology could be employed to specifically target CD4⁺ T cells or virally-infected T cells. Right panel: patient- or donor-derived naïve-like T cells can be used to generate and in vitro expand T_SCM with or without gene engineering. Gene modifications include the insertion of tumor or virus-specific chimeric antigen receptor (CAR) or T cell receptor (TCR) genes, tumor or virus-specific TCR gene editing, suicide gene transfer in the context of donor lymphocyte infusion following hematopoietic stem cell transplantation, and CCR5 deletion in the setting of HIV-1 infection. Virus-specific T_SCM can also be expanded from the naturally-occurring antigen-specific TCR repertoire through in vitro sensitization protocols favoring the generation of T_SCM. T_N, naïve T cell; T_CM, central memory T cell; APC, antigen presenting cell.