HAVCR2

HAVCR2 Full Name

hepatitis A virus cellular receptor 2

HAVCR2 Introduction

T cell immunoglobulin and mucin domain containing 2 (TIMD2), also known as TIM-2, is a member of the T cell immunoglobulin and mucin domain (TIM) gene family, a group of type I transmembrane glycoproteins involved in the regulation of immune responses. The human TIM gene family is located on chromosome 5q33.2 and includes three functional members (TIM-1, TIM-3, TIM-4) and a pseudogene. TIMD2/TIM-2 is a functional gene in mice but is reported to be a pseudogene in humans due to a premature stop codon, although its transcript and potential non-coding functions continue to be investigated. Mouse TIM-2 is expressed on activated T cells, B cells, and dendritic cells, where it functions as a negative regulator of immune responses.

Figure 1. Strcuture of HAVCR2.

Ligand Recognition and Immunomodulatory Functions of Mouse TIM-2
Mouse TIM-2 has been characterized as a receptor for semaphorin-4A (Sema4A), a member of the semaphorin family of membrane-bound and secreted guidance molecules with immunoregulatory functions. The TIM-2/Sema4A interaction delivers inhibitory signals that attenuate T cell activation and Th1/Th17 differentiation while promoting the development of regulatory T cell responses. TIM-2 also binds ferritin H chain with high affinity, mediating the uptake and cellular delivery of iron-loaded ferritin — an unexpected function that links iron metabolism to immune regulation. Through this ferritin-binding activity, TIM-2 may serve as a checkpoint that couples systemic iron status to the intensity of immune responses. The cytoplasmic tail of TIM-2 contains a conserved tyrosine phosphorylation motif that, when phosphorylated, can recruit SH2 domain-containing signaling proteins, though the downstream signaling pathways remain less fully defined than those of the prototypical family member TIM-3.

TIM-2 in Autoimmunity, Allergic Disease, and the Human TIMD2 Pseudogene
In mice, TIM-2 functions as a negative regulator of Th2-driven allergic inflammation: Tim2-deficient mice exhibit exaggerated Th2 responses and increased susceptibility to allergic airway inflammation in models of asthma, consistent with an inhibitory role in allergic disease pathogenesis. Polymorphisms in the mouse Tim gene family (including Tim2) have been linked to differential susceptibility to experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. In humans, the status of TIMD2 as a pseudogene raises intriguing evolutionary questions: the loss of this immunoregulatory receptor in the human lineage, while retained in rodents, indicates species-specific differences in immune regulatory mechanisms at the TIM locus. The human TIMD2 pseudogene may produce non-coding RNA transcripts with potential regulatory functions, though this remains speculative. A comprehensive understanding of TIMD2 biology requires consideration of both its functional roles in model organisms and the evolutionary trajectory of the human locus.

Alternate Names for HAVCR2

HAVCR2; hepatitis A virus cellular receptor 2; TIM3; KIM-3; TIMD3; Tim-3; TIMD-3; HAVcr-2; kidney injury molecule-3; T-cell membrane protein 3