The Stem of T Cell Memory

RESEARCH HIGHLIGHTS

T CELL MEMORY The stem of T cell memory

Effector memory T (TEM) cells are antigen 1 (SCA1), B cell lymphoma 2 which suggests that these cells have terminally differentiated and acquire (BCL‑2) and CXC-chemokine a self-renewal capacity. By contrast, these self- effector function immediately after receptor 3 (CXCR3), and can be following TCR stimulation, most re-stimulation, whereas central induced through activation of the T cells gradually acquired a T renewing, SCM CM memory T (T ) cells have a longer WNT signalling pathway. In search phenotype, some of them differenti- multipotent CM lifespan and can differentiate into of a human memory T cell subset ated into TEM cells and approximately

human TSCM TEM cells following antigenic chal- with analogous properties, Gattinoni 15% of them maintained their initial cells have lenge. A recent study published in et al. stimulated ex vivo-isolated phenotype, indicating that TSCM cells an improved Nature Medicine reports that an human naive T cells in the presence are multipotent. additional memory T cell subset, of the WNT pathway activator So, do these self-renewing, therapeutic T memory stem (TSCM) cells, which TWS119 and observed upregulation multipotent human TSCM cells have potential was previously identified in mice, of CD95 (also known as FAS) and an improved therapeutic potential compared exists in humans and exhibits stem the memory-associated marker compared with TCM and TEM cells? cell properties. CD122 in the treated T cells, which Similarly to their mouse counter- with TCM and Mouse TSCM cells have a naive- retained a naive-like phenotype in parts, human TSCM cells proliferated T cells low hi EM like CD44 CD62L phenotype, other respects. Thus, they hypoth- more vigorously than TCM and TEM express the CD122 (a component esized that CD95 may be a marker cells following TCR stimulation

of the IL-15 receptor), stem cell for human TSCM cells. in vitro. Moreover, human TSCM cells Indeed, flow cytometric analysis were found to survive longer than

of human peripheral blood identified TCM and TEM cells after adoptive naive-like CD4+ and CD8+ T cells transfer into immunodeficient mice. with the CD95+CD122+ phenotype Finally, a comparison of the thera- and high levels of expression of peutic potential of in vitro-generated

BCL‑2 and CXCR3. Like TCM and human TEM, TCM and TSCM cells (all of

TEM cells, human TSCM cells were found which were engineered to express a to have undergone clonal expansion chimeric TCR specific for a tumour

and to be long-lived, and they rapidly antigen) indicated that TSCM cells acquired effector function following — which were induced by pharma T cell receptor (TCR) stimulation. cological activation of the WNT The gene expression pattern of pathway — were the most effective

TSCM cells indicated that they are T cells in terms of survival and a distinct population of memory tumour clearance after transfer T cells that are less differentiated into tumour-bearing mice. This

than TCM and TEM cells. potential to generate engineered

Interestingly, human TSCM cells human TSCM cells in vitro opens new proliferated robustly in response to avenues for cancer immunotherapy. interleukin‑15 stimulation (which Maria Papatriantafyllou is an attribute of memory but not naive T cells), but the majority of ORIGINAL RESEARCH PAPER Gattinoni, L. et al. proliferating T cells maintained A human memory T cell subset with stem cell-like SCM properties. Nature Med. 17, 1290–1297 (2011) CORBIS their initial naive-like phenotype,