The role of coinhibitory receptor-expressing non-T cells in inflammation and immunity: unsung heroes or peripheral players?

Immune responses are finely regulated by multiple mechanisms, among which immune regulatory coreceptor family molecules play a central role in both enhancing and suppressing immune responses. Traditionally, T cells have been considered the primary cell type expressing these receptors, through which their responses are modulated. This understanding led to the emergence of the field of 'immune checkpoint blockade', which aims to rejuvenate T cells that have become exhausted in the context of chronic infections or the tumor environments. The molecules targeted by such approaches include PD1, CTLA4, Lag3, Tim3 and TIGIT, coinhibitory receptors predominantly expressed on conventional T cells exhibiting functionally impaired, exhausted phenotypes. Interestingly, an expanding array of non-T cell types also express these receptors, although their specific roles remain largely elusive. Here we explore the immune regulatory functions of these coreceptors as expressed on non-conventional T cells, such as myeloid cells and B cells, highlighting their potential contributions to immune regulation.