Effector memory T (TEM) cells are terminally differentiated and acquire effector function immediately after re-stimulation, whereas central memory T (TCM) cells have a longer lifespan and can differentiate into TEM cells following antigenic challenge. A recent study published in Nature Medicine reports that an additional memory T cell subset, T memory stem (TSCM) cells, which was previously identified in mice, exists in humans and exhibits stem cell properties.
“these self-renewing, multipotent human TSCM cells have an improved therapeutic potential compared with TCM and TEM cells”
Mouse TSCM cells have a naive-like CD44lowCD62Lhi phenotype, express the CD122 (a component of the IL-15 receptor), stem cell antigen 1 (SCA1), B cell lymphoma 2 (BCL-2) and CXC-chemokine receptor 3 (CXCR3), and can be induced through activation of the WNT signalling pathway. In search of a human memory T cell subset with analogous properties, Gattinoni et al. stimulated ex vivo-isolated human naive T cells in the presence of the WNT pathway activator TWS119 and observed upregulation of CD95 (also known as FAS) and the memory-associated marker CD122 in the treated T cells, which retained a naive-like phenotype in other respects. Thus, they hypothesized that CD95 may be a marker for human TSCM cells.
Indeed, flow cytometric analysis of human peripheral blood identified naive-like CD4+ and CD8+ T cells with the CD95+CD122+ phenotype and high levels of expression of BCL-2 and CXCR3. Like TCM and TEM cells, human TSCM cells were found to have undergone clonal expansion and to be long-lived, and they rapidly acquired effector function following T cell receptor (TCR) stimulation. The gene expression pattern of TSCM cells indicated that they are a distinct population of memory T cells that are less differentiated than TCM and TEM cells.
Interestingly, human TSCM cells proliferated robustly in response to interleukin-15 stimulation (which is an attribute of memory but not naive T cells), but the majority of proliferating TSCM cells maintained their initial naive-like phenotype, which suggests that these cells have a self-renewal capacity. By contrast, following TCR stimulation, most TSCM cells gradually acquired a TCM phenotype, some of them differentiated into TEM cells and approximately 15% of them maintained their initial phenotype, indicating that TSCM cells are multipotent.
So, do these self-renewing, multipotent human TSCM cells have an improved therapeutic potential compared with TCM and TEM cells? Similarly to their mouse counterparts, human TSCM cells proliferated more vigorously than TCM and TEM cells following TCR stimulation in vitro. Moreover, human TSCM cells were found to survive longer than TCM and TEM cells after adoptive transfer into immunodeficient mice.
Finally, a comparison of the therapeutic potential of in vitro-generated human TEM, TCM and TSCM cells (all of which were engineered to express a chimeric TCR specific for a tumour antigen) indicated that TSCM cells — which were induced by pharmacological activation of the WNT pathway — were the most effective T cells in terms of survival and tumour clearance after transfer into tumour-bearing mice. This potential to generate engineered human TSCM cells in vitro opens new avenues for cancer immunotherapy.
ORIGINAL RESEARCH PAPER
Gattinoni, L. et al. A human memory T cell subset with stem cell-like properties. Nature Med. 17, 1290–1297 (2011)
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Evaluation of antiviral T cell responses and TSCM cells in volunteers enrolled in a phase I HIV-1 subtype C prophylactic vaccine trial in India
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