T cell immunoglobulin and mucin domain 1 (TIM-1), also known as Kidney injury molecule 1
(KIM-1) and Hepatitis A virus cellular receptor 1 (HAVcr1), is a member of the TIM family which
is involved in the regulation of innate and adaptive immune responses (1, 2). TIM-1 is a
type I transmembrane protein that contains an N-terminal immunoglobulin-like domain,
a mucin domain with O- and N-linked glycosylations, a transmembrane segment, and
a cytoplasmic signaling domain (3, 4). Multiple TIM-1 variants can be produced due to
polymorphisms or alternative splicing resulting in deletions in the mucin domain (3). Some of
these polymorphisms are associated with susceptibility to atopy, autoimmunity, and severe
hepatitis A virus infection in humans (5). Within the extracellular domain, human TIM-1 shares
41% amino acid sequence identity with mouse and rat TIM-1.
In vivo, TIM-1 is expressed on splenic B cells and is a marker for the identification of IL-10+
regulatory B cells (6, 7). TIM-1 is also expressed on CD4+ T cells, mast cells, invariant NKT (iNKT)
cells, dendritic cells, kidney epithelium and a broad range of mucosal epithelium (4, 8-15). The
expression of TIM-1 is upregulated on activated Th2 cells, after dendritic cell maturation, and
on kidney tubular epithelial cells after injury (4, 9, 13, 14, 16, 17). Metalloproteinase-mediated
cleavage of TIM-1 at the membrane-proximal region results in the release of a soluble form
of TIM-1 which is detectable in the urine and in circulation (18, 19). Urinary TIM-1 is highly
elevated in nephropathy and may be a useful biomarker for renal damage (16, 20 - 25).
TIM-1 has been reported to be a receptor for a number of ligands, including
phosphatidylserine, leukocyte mono-immunoglobulin-like receptor 5 (LMIR5/CD300b), TIM-1
(homophilic), TIM-4, IgA, and the glycoproteins of a number of enveloped viruses (5, 15, 26-33).
Its interaction with phosphatidylserine enables TIM-1 to mediate the phagocytosis of apoptotic
cells (26-28). In TIM-1-bearing iNKT cells, interaction with apoptotic cells can also result in iNKT
cell activation, proliferation, and cytokine production (11). Interactions between cell-surface
or soluble TIM-1 with LMIR5 is proposed to induce LMIR5-mediated activation of myeloid cells
including macrophages/monocytes, mast cells, neutrophils, and dendritic cells (29). These
interactions contribute to tissue homeostasis and damage during kidney injury (29). Ligandinduced TIM-1 signaling costimulates T cell activation and enhances Th2 cytokine production
(9, 31, 34). In humans, TIM-1 serves as a cellular entry receptor for various viruses, including
hepatitis A virus, Ebolavirus and Marburgvirus (15, 33).