Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells

Abstract

Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways1. Wnt/β-catenin is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation2,3, but its role in the generation and maintenance of memory T cells is unknown. We found that the induction of Wnt/β-catenin signaling using inhibitors of glycogen-sythase-kinase-3β or the Wnt protein family member, Wnt3a, arrested CD8+ T cell development into effector cells. By blocking T-cell differentiation, Wnt signaling enabled the generation of CD44low, CD62Lhigh, Sca-1high, CD122high, Bcl-2high self-renewing, multipotent CD8+ memory stem cells with proliferative and anti-tumor capacities exceeding those of central and effector memory T cell subsets. These findings reveal a key role for Wnt signaling in the maintenance of stemness in mature memory CD8+ T cells and have important implications for the design of novel vaccination strategies and adoptive immunotherapies.

Adoptively transferred effector cells derived from naïve rather than central memory CD8 + T cells mediate superior antitumor immunity

“…In our studies, T EFF CM but not T EFF N acquired KLRG1 expression in vitro and in vivo reflecting a greater tendency of this effector cell lineage to develop phenotypic senescence and suggesting a mechanism for the diminished expansion of these cells that occurred following infusion. These findings further imply that the fate of short-or long-lived effector cells might be linked to their origin as naïve or memory T cells and underscore that the prevention of terminal differentiation, which can be accomplished using IL-21 or Wnt, is desirable in the generation of T-cell populations for adoptive immunotherapy (21,31).…”

“…Previous studies on the influence of CD8 ϩ T cell differentiation states have not focused on the relative efficacy of naïve T cells (20)(21)(22)(23). With the emergence of TCR gene therapy, naïve cells, which represent the most common CD8 ϩ T-cell phenotype in many patients, have become an important potential source of effector cells.…”

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

“…18 Interestingly, while expansion was not hampered by inhibiting AKT, generation of early memory cells by interference with GSK-3β clearly blocked proliferation of T cells. 15,30,33 This makes AKT a very potent candidate for the generation of effective adoptive T cell products.…”

T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy

“…To assess whether a threshold for maximal antitumor activity also exists in vivo in the ACT setting (35,39,47,48), we treated A2-K b transgenic mice bearing B16/A2-K b melanoma by a combination of vaccination with gp209-2M fowlpox virus (49) and with CD8+ T cells transduced with selected TCRs (16LD6, R6C12, 5CE2, K4H5, L2G2, and W2C8) representing the entire avidity/affinity range. Treatment with CD8+ splenocytes expressing the low-affinity/-avidity TCR W2C8 did not result in differences in tumor growth compared with the untreated group (Fig.…”