Old but gold: ILC-induced T-cell senescence prevents GVHD Free

In this issue of Blood,Tufa et al¹ demonstrate that innate lymphoid cells (ILCs) mitigate graft-versus-host disease (GVHD) by inducing T-cell senescence via interleukin-9 (IL-9), thereby reducing T-cell proliferation.

ILCs are lymphocytes that lack rearranged antigen-specific receptors.² They are classified into 5 subsets: natural killer (NK) cells, lymphoid tissue inducer (LTi) cells, and the more recently defined group of noncytotoxic ILC1s, ILC2s, and ILC3s.² This latter group is predominantly tissue-resident and is considered the innate counterpart of CD4⁺ T helper (Th) cells, with ILC1s, ILC2s, and ILC3s mirroring the cytokine profiles of Th1, Th2, and Th17/Th22 cells, respectively.² ILCs play a crucial role in maintaining tissue homeostasis and initiating immune responses.² 

The growing understanding of ILCs and their interactions with immune, epithelial, and stromal cells has raised the interest in their ability to modulate GVHD. GVHD is a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) that occurs when immunocompetent donor T cells recognize recipient antigens as foreign and generate an immune response that damages recipient tissues.³ Preclinical and clinical studies have demonstrated that ILCs can offer protection from GVHD.^4-8 In a murine model, recipient-derived ILC3s reduced gastrointestinal (GI) GVHD by producing IL-22, which protected intestinal stem cells and epithelial cells from inflammatory injury.⁴ Infusion of donor ILC2s was effective in preventing and treating GI GVHD through IL-13–mediated accumulation of donor myeloid-derived suppressor cells (MDSCs) and amphiregulin-dependent maintenance of the epithelial barrier.⁵ Clinical studies further showed that higher frequencies of activated recipient or donor ILCs before or after allo-HCT, respectively, were associated with reduced risk of GVHD.⁶ Similarly, the frequency of ILCs in allo-HCT grafts inversely correlated with GVHD incidence.⁷ A recent study reported that human ILC3s expressing the ectoenzymes CD39 and CD73 suppressed autologous T-cell proliferation, suggesting that depletion of these ILC3s in gut tissue of patients with GVHD may contribute to uncontrolled tissue damage.⁸ 

Despite the expanding knowledge on ILCs, it remains to be explored whether and how ILCs modulate T cells in an alloreactive setting. In the present study, Tufa et al address this question using a series of in vitro assays as well as xenogeneic and allogeneic GVHD mouse models. ILC2s and ILC3s impaired T-cell proliferation in a cell contact–independent manner and increased the proportions of central memory T cells (T_CM) and stem cell memory T cells (T_SCM). T cells cocultured with ILC2s or ILC3s increased expression of senescence-associated surface markers, including CD57, KLRG1, TIGIT, and TIM3. These T cells also exhibited changes in regulatory protein expression indicative of cell cycle arrest, specifically upregulation of p16, p21, and p53, and downregulation of c-Myc. Additionally, T cells displayed a senescence-associated secretory phenotype (SASP), characterized by the production of multiple cytokines, including IFN-γ, TNF-α, IL-2, IL-10, IL-13, IL-9, and IL-22. Mechanistically, the study identified IL-9 produced by hematopoietic stem cell (HSC)–derived ILCs as a key mediator in inducing T-cell senescence and reducing T-cell proliferation. IL-9 blockade reversed these effects, whereas the addition of exogenous IL-9 to T cells mimicked the impact of an ILC coculture. Adoptive transfer of human HSC–derived ILCs improved GVHD in a xenogeneic mouse model. Similarly, murine ILCs derived from common lymphoid progenitor cells prevented GVHD in an allogeneic murine model without impacting graft-versus-tumor effects.

In summary, the study identifies T-cell senescence induced by ILC-derived IL-9 as a mechanism to mitigate GVHD. Future investigations are needed to clarify the downstream signaling pathways through which IL-9 promotes T-cell senescence. ILC-derived IL-9 may also have indirect effects on T cells by impacting other immune-cell subsets in vivo. Additionally, factors specific to the tissue environment, such as cross talk with nonhematopoietic cells, microbiota composition, and local cytokines, may promote context-dependent differences between ILC2 and ILC3 function, adding complexity beyond the controlled conditions of experimental models. Furthermore, given that senescence is closely linked to aging, studies using T cells from older donors are warranted to explore whether age affects ILC-mediated modulation of GVHD.

Although certain questions remain, the study by Tufa et al builds a strong foundation for future investigations by providing the first in vitro and in vivo evidence that ILCs can influence the fate of alloreactive T cells. It expands the current understanding of ILCs beyond tissue protection and highlights their potential to directly shape alloreactive T-cell responses. ILC-mediated T-cell modulation may represent a promising therapeutic strategy for GVHD, as functional reprogramming of T cells may offer a more targeted approach than broad immunosuppression. These insights hold promising translational potential and support further clinical investigation.

Conflict-of-interest disclosure: The author declares no competing financial interests.