The Janus face of group 3 innate lymphoid cells (ILC3s). ILC3s are highly plastic and can adapt their immunoregulatory roles according to the local context, balancing tolerance and activation. Influenced by tissue-specific environmental cues, they can express MHC class II molecules either alone or jointly with costimulatory molecules, therefore presenting acquired antigens for controlling or triggering CD4⁺ T cell activities.

ABSTRACT

Group 3 innate lymphoid cells (ILC3s) are tissue-resident lymphocytes distributed across both lymphoid and non-lymphoid tissues, capable of mounting rapid immune responses. They are defined by expression of the transcription factor RORγt and comprise distinct subsets, including lymphoid tissue inducer-like cells expressing major histocompatibility complex class II (MHCII). These MHCII⁺ ILC3s can directly present antigens to CD4⁺ T cells, a function regulated by the transcriptional activator CIITA through a pathway similar to thymic epithelial cells. ILC3s contribute to immune homeostasis by limiting effector T cell responses and promoting regulatory T cell differentiation. However, under the influence of distinct cytokine milieus, such as IL-1β and IFN-γ, ILC3s undergo a maturation process, upregulating costimulatory molecules and enhancing their antigen-presenting capacity to activate CD4⁺ T cells. This dual functionality is highly plastic and influenced by tissue-specific environmental cues, enabling ILC3s to adapt their immunoregulatory roles according to local context. Overall, ILC3s now emerge as critical modulators of T cell activities, balancing tolerance and activation, with significant implications for host defense, autoimmunity, inflammation, and cancer.