Human disease mutations highlight the inhibitory function of TIM-3

Abstract

A new study identifies loss-of-function mutations in HAVCR2, which encodes TIM-3, in patients with a rare cutaneous T cell lymphoma associated with aberrant immunological activation. These mutations lead to loss of the TIM-3 immunological checkpoint, thus promoting inflammation and malignancy.

Fig. 1 |. TIM-3 deficiency leads to uncontrolled immunological activation resulting in T cell malignancy and autoinflammation.

In unaffected individuals, Gal-9-driven TIM-3 signaling in immune cells tunes and shapes activating signals, thereby limiting autoimmunity and maintaining immunological homeostasis. Two mutant variants in the galectin-binding residues of TIM-3 (Y82C and I97M) observed in patients with SPTCL induce TIM-3 misfolding, thereby preventing its plasma membrane expression. This lack of expression leads to persistent immune activation, owing to a lack of intrinsic TIM-3 signaling in CD8 T cells, and impaired T_reg function failing to regulate these overactive T cells. In myeloid cells, the misfolded TIM-3 molecules induce activation of the NLRP3 inflammasome, thus resulting in release of proinflammatory cytokines (IL-1β and IL-18). As in T cells, the lack of intrinsic TIM-3 signaling in myeloid cells results in hyperactive myeloid cells with enhanced production of TNFα. Together, these effects propagate a positive feed-forward mechanism that further amplifies inflammatory responses and results in the production of autoantibodies from B cells and induction of uncontrolled proliferation of effector T cells, thus culminating in adipose tissue infiltration of lymphocytes and T cell lymphoma. TCR, T cell receptor; BCR, B cell receptor; MHC, major histocompatibility complex; sCD25, soluble IL-2 receptor; dsDNA, double-stranded DNA.