Immune Regulation by the TIM Gene Family

Souza, Anjali J. de; Kane, Lawrence P.

doi:10.1385/ir:36:1:147

Cited by 17 publications

(13 citation statements)

References 37 publications

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“…We do not believe that our results can be attributed merely to overexpression in a particular cell line. First, our previous studies of the Tim family proteins Tim-1 and Tim-2 with this system have yielded results largely consistent with those obtained with other approaches (12,14,19,30). Also, although many of our reporter activation studies were initially carried out with the Jurkat human leukemic line, we have validated our findings with a nontransformed murine T-cell clone (D10) that, like Jurkat, does not express endogenous Tim-3.…”

Section: Discussionsupporting

confidence: 85%

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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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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Section: Discussionsupporting

confidence: 85%

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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232

277

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“…Since some ISR have only a modest phenotype when the gene is deleted in mice (e.g. Tim3 [67]), any undesirable consequences of blockade will similarly depend on the specific ISR targeted.…”

Section: Inhibitory Signaling Receptor Expression In Til Mediates Dysmentioning

confidence: 99%

Suppression of T cell responses in the tumor microenvironment

Frey

2015

Vaccine

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“…Of these family members, TIM-1 has been implicated in the immune regulation of asthma and atopic diseases (3,4). More recent studies have shown that ligation of TIM-1 with an agonistic Ab or with a ligand (TIM-4) can costimulate proliferation of T cells as well as cytokine production, both in vivo and in vitro, and abrogate tolerance in a Th2 model of respiratory tolerance, collectively suggesting that it usually functions as a positive immune regulator (5,6).…”

Section: P Roteins Of the T Cell Ig And Mucin Domain (Tim) 3 Familymentioning

confidence: 99%

T Cell Ig and Mucin Domain-1-Mediated T Cell Activation Requires Recruitment and Activation of Phosphoinositide 3-Kinase

Souza

Oak

Jordanhazy

et al. 2008

The Journal of Immunology

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Ligation of the transmembrane protein T cell Ig and mucin domain (Tim)-1 can costimulate T cell activation. Agonistic Abs to Tim-1 are also capable of inducing T cell activation without additional stimuli. However, little is known about the biochemical mechanisms underlying T cell stimulation or costimulation through Tim-1. We show that a tyrosine in Tim-1 becomes phosphorylated in a lck-dependent manner, whereupon it can directly recruit p85 adaptor subunits of PI3K. This results in PI3K activation, which is required for Tim-1 function. We also provide genetic evidence that p85 expression is required for optimal Tim-1 function. Thus, we describe a pathway from Tim-1 tyrosine phosphorylation to the PI3K signaling pathway, which appears to be a major effector of Tim-1-mediated T cell activation.

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Immune Regulation by the TIM Gene Family

Cited by 17 publications

References 37 publications

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

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

Suppression of T cell responses in the tumor microenvironment

T Cell Ig and Mucin Domain-1-Mediated T Cell Activation Requires Recruitment and Activation of Phosphoinositide 3-Kinase

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