We read with interest the paper by Gorman et al. (1) that challenges the function of Tim-3 as an inhibitory receptor (1). In this paper, the authors examine the role of Tim-3 using OVA-expressing Listeria monocytogenes and a newly generated Tim-3–deficient mouse. The authors find that in the absence of Tim-3 the expansion of OVA-specific T cells is blunted as are CD8 T cell effector functions (IFN-γ production and degranulation). From these data, the authors come to the conclusion that Tim-3 does not inhibit but rather enhances CD8 T cell responses. Unfortunately, the Tim-3 knock-out mouse generated for the study is flawed to use to make such conclusions. The Tim family of genes is encoded in a contiguous locus in the mouse. Tim-1, Tim-3, and Tim-4 are polymorphic in the mouse and these polymorphisms are associated with differences in immune responses (2, 3). The authors targeted the Tim-3 locus in 129 embryonic stem cells and then crossed the targeted allele onto the C57BL/6 background. Because the 129 haplotype differs from that in C57BL/6, all of the polymorphisms in the adjacent Tim genes were crossed over from 129 onto C57BL/6. The Tim genes have important documented roles in regulating the T cell response and the polymorphisms in the different Tims have been demonstrated to impact on the function of Tim family members. For example, polymorphisms in Tim-1 in BALB/c (same haplotype as 129) and DBA/2 (same haplotype as C57BL/6) have been shown to have profound effects on immune responses (4). Thus, the carryover of Tim polymorphisms from 129 to B6 is an important confounding variable in the Tim-3 knockout mouse used by Gorman et al. Unless a control Tim locus from 129 is transferred to C57BL/6 and used as a control in these experiments, the results cannot be ascribed simply to the loss of Tim-3 in the knock-out mouse. Although it is true that there are still many things about Tim-3 that are not known and that additional research is required to increase our understanding of the mechanisms by which this important molecule regulates T cell function, this study does not invalidate all of the previous work showing that Tim-3 functions as an inhibitory receptor.
- Copyright © 2014 by The American Association of Immunologists, Inc.
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