Cutting Edge: Inhibition of T Cell Activation by TIM-2

Knickelbein, Jared E.; Souza, Anjali J. de; Tosti, Richard; Narayan, Preeti; Kane, Lawrence P.

doi:10.4049/jimmunol.177.8.4966

Cited by 37 publications

(40 citation statements)

References 22 publications

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“…Second, the murine TAPR locus contains five genes that are absent from the human locus, including TIM-2 which is very closely homologous to TIM-1 (1). We and others have shown that TIM-2 is a negative regulator of T cell activity (15,16,21) and a recent study has shown that TIM-2 can function by blocking CD3/CD28-mediated costimulation of T cells (21). It is possible that TIM-2 acts to block TIM-1-mediated signaling in mice as well.…”

Section: Discussionmentioning

confidence: 99%

Human TIM-1 Associates with the TCR Complex and Up-Regulates T Cell Activation Signals

Binné

Scott

Rennert

2007

The Journal of Immunology

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The T cell, Ig domain, and mucin domain-1 (TIM-1) gene is associated with Th2 T cell responses and human atopic diseases. The mechanism by which TIM-1 influences T cell responses remains unknown. We demonstrate that TIM-1 is recruited to the TCR-signaling complex via association with CD3. TIM-1 up-regulates TCR-associated signaling events, including phosphorylation of Zap70 and IL-2-inducible T cell kinase. This activity requires TIM-1 tyrosine phosphorylation. TIM-1 expression induces formation of a novel complex that includes PI3K and ITK. Finally, the consequences of TIM-1 activation include increased expression of effector cytokines. These results demonstrate that TIM-1 is a critical component of the human T cell response and provide a mechanistic hypothesis for the role of TIM-1 in disease.

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Section: Discussionmentioning

confidence: 99%

Human TIM-1 Associates with the TCR Complex and Up-Regulates T Cell Activation Signals

Binné

Scott

Rennert

2007

The Journal of Immunology

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“…Jurkat, D10, and 293T cells were cultured and transiently transfected as previously described (14,19,22). Luciferase assays were conducted as described previously (18,22).…”

Section: Methodsmentioning

confidence: 99%

“…Luciferase reporter constructs have been described previously (14,19). Wild-type murine Tim-3 cDNA was obtained by reverse transcription-PCR (RT-PCR), starting with whole-spleen RNA made from C57BL/6 mice.…”

Section: Methodsmentioning

confidence: 99%

Phosphotyrosine-Dependent Coupling of Tim-3 to T-Cell Receptor Signaling Pathways

Lee

Zhu

et al. 2011

Molecular and Cellular Biology

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237

277

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The transmembrane protein Tim-3 has been shown to negatively regulate T-cell-dependent immune responses and was recently demonstrated to be associated with the phenomenon of immune exhaustion, which can occur as a consequence of chronic viral infection. Unlike other negative regulators of T-cell function (e.g., PD-1), Tim-3 does not contain any obvious inhibitory signaling motifs. We have found that ectopic expression of Tim-3 in T cells leads to enhancement of T-cell receptor (TCR)-dependent signaling pathways, which was observed at the level of transcriptional reporters and endogenous cytokine production. We have exploited this observation to dissect what elements within the cytoplasmic tail of Tim-3 are required for coupling to downstream signaling pathways. Here we have demonstrated that two of the more membrane-proximal cytoplasmic tail tyrosines are required for Tim-3 signaling to T-cell activation pathways in a redundant fashion. Furthermore, we show that Tim-3 can directly bind to the Src family tyrosine kinase Fyn and the p85 phosphatidylinositol 3-kinase (PI3K) adaptor. Thus, at least under conditions of short-term stimulation, Tim-3 can augment T-cell activation, although this effect can be blocked by the inclusion of an agonistic antibody to Tim-3. These findings should help further the study of Tim-3 function in other physiological settings, such as those that lead to immune exhaustion.During the expansion phase of an immune response to acute infection, newly activated antigen-specific T cells expand rapidly and acquire effector functions. This is then followed by a period of contraction, where all but 5 to 10% of these effector T cells succumb to apoptosis. The remaining T cells constitute the memory pool-multifunctional T cells that persist in the host in an antigen-independent manner with the ability to respond quickly upon reexposure to viral antigen. However, during chronic viral infection, effector CD8 ϩ T cells generated during the expansion phase fail to develop into memory CD8 ϩ T cells. Instead, these effector CD8 ϩ T cells appear to become exhausted (2, 33).T-cell exhaustion is characterized as the progressive and stepwise loss of the ability to secrete interleukin 2 (IL-2), tumor necrosis factor alpha (TNF-␣), and gamma interferon (IFN-␥) in response to antigenic stimulation, culminating (in the most extreme cases) in apoptosis (33). This system of clonal deletion has been documented under conditions of persistent antigen stimulation, such as high-grade chronic viral infections in both mouse and human and, most recently, in patients with advanced melanoma. Exhausted CD8 ϩ T cells have a distinct molecular signature that resembles that of effector T cells more than that of memory T cells (34). Of the several hundred genes differentially upregulated in exhausted CD8 ϩ T cells, some are inhibitory receptors, such as CTLA-4, LAG-3, and PD-1. Several studies have confirmed that PD-1 is upregulated on exhausted CD4 ϩ and CD8 ϩ T cells (4, 6, 7, 10). However, blocking the interaction between PD...

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“…The first involves a receptor identical to TIM-2 (member of the T-cell immunoglobulin and mucin-domain gene family) that specifically binds extracellular H-subunit rich ferritins followed by the internalization of H-subunit rich ferritins, and is expressed in B-cells and in non-haematopoietic organs such as the liver and kidney. Internalization of the H-subunit rich ferritins resulted in immunosuppression by inhibiting T-cell activation (Knickelbein et al, 2006). The second receptor that binds H-subunit rich ferritins is transferrin receptor 1.…”

Section: Immune Modulation By Secreted H-subunit Rich Ferritinsmentioning

confidence: 99%