SMUCKLER/TIM4 is a distinct member of TIM family expressed by stromal cells of secondary lymphoid tissues and associated with lymphotoxin signaling.

Lymphotoxin-alpha (LTalpha) was originally linked to delayed-type hypersensitivity and its production was later attributed to Th1, but not Th2 cells. Studies employing knockout mice demonstrated that LT signaling is essential for the development and functional compartmentalization of lymphoid tissues. Here, using gene expression profiling, we identified a novel gene termed SMUCKLER (spleen, mucin-containing, knockout of lymphotoxin), that is selectively down-regulated in spleens of LTalpha- or LTbeta-deficient mice. The encoded transmembrane protein contains immunoglobulin V and mucin domains and is identical to TIM4, a predicted member of recently identified TIM family (T cell immunoglobulin- and mucin-domain-containing molecule). Unlike TIM1 and TIM3, which were implicated in T cell-mediated functions, SMUCKLER lacks tyrosine phosphorylation motif in its intracellular domain and is not expressed by bone marrow-derived cells. In situ hybridization of spleen sections demonstrated SMUCKLER expression by stromal cells predominantly in the marginal zone and to a lesser extent throughout the white pulp. Similarly to other TIM genes, SMUCKLER maps to a locus associated with predisposition to asthma both in mice and in humans (11.b1 and 5q33, respectively) and shows coding sequence variations between BALB/c and DBA mice. Therefore, SMUCKLER/TIM4 may be considered as a candidate disease-predisposition gene for asthma.