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

Souza, Anjali J. de; Oak, Jean; Jordanhazy, Ryan; DeKruyff, Rosemarie H.; Fruman, David A.; Kane, Lawrence P.

doi:10.4049/jimmunol.180.10.6518

Cited by 62 publications

(104 citation statements)

References 43 publications

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“…This finding is reminiscent of previous work on another Tim family member, Tim-1. For example, we showed that Tim-1 also requires proximal T-cell receptor signaling machinery in order to activate NFAT/AP-1 (13). In addition, it has been reported that in human T cells, Tim-1 can be cocapped with the TCR/CD3 complex (5).…”

Section: Discussionmentioning

confidence: 93%

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: Discussionmentioning

confidence: 93%

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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“…Unlike TIM-1 and TIM-3, TIM-4 does not have a known signaling motif in its cytoplasmic tail (30,(53)(54)(55)(56). Additionally, TIM-4-mediated engulfment of apoptotic cells has been shown not to involve the ELMO1/DOCK180/Rac or GULP signaling pathway (30).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Human and Murine T-Cell Immunoglobulin Mucin Domain 4 (TIM-4) IgV Domain Residues Critical for Ebola Virus Entry

Rhein

Brouillette

Schaack

et al. 2016

J Virol

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Phosphatidylserine (PtdSer) receptors that are responsible for the clearance of dying cells have recently been found to mediate enveloped virus entry. Ebola virus (EBOV), a member of the Filoviridae family of viruses, utilizes PtdSer receptors for entry into target cells. The PtdSer receptors human and murine T-cell immunoglobulin mucin (TIM) domain proteins TIM-1 and TIM-4 mediate filovirus entry by binding to PtdSer on the virion surface via a conserved PtdSer binding pocket within the amino-terminal IgV domain. While the residues within the TIM-1 IgV domain that are important for EBOV entry are characterized, the molecular details of virion-TIM-4 interactions have yet to be investigated. As sequences and structural alignments of the TIM proteins suggest distinct differences in the TIM-1 and TIM-4 IgV domain structures, we sought to characterize TIM-4 IgV domain residues required for EBOV entry. Using vesicular stomatitis virus pseudovirions bearing EBOV glycoprotein (EBOV GP/ VSV⌬G), we evaluated virus binding and entry into cells expressing TIM-4 molecules mutated within the IgV domain, allowing us to identify residues important for entry. Similar to TIM-1, residues in the PtdSer binding pocket of murine and human TIM-4 (mTIM-4 and hTIM-4) were found to be important for EBOV entry. However, additional TIM-4-specific residues were also found to impact EBOV entry, with a total of 8 mTIM-4 and 14 hTIM-4 IgV domain residues being critical for virion binding and internalization. Together, these findings provide a greater understanding of the interaction of TIM-4 with EBOV virions. IMPORTANCEWith more than 28,000 cases and over 11,000 deaths during the largest and most recent Ebola virus (EBOV) outbreak, there has been increased emphasis on the development of therapeutics against filoviruses. Many therapies under investigation target EBOV cell entry. T-cell immunoglobulin mucin (TIM) domain proteins are cell surface factors important for the entry of many enveloped viruses, including EBOV. TIM family member TIM-4 is expressed on macrophages and dendritic cells, which are early cellular targets during EBOV infection. Here, we performed a mutagenesis screening of the IgV domain of murine and human TIM-4 to identify residues that are critical for EBOV entry. Surprisingly, we identified more human than murine TIM-4 IgV domain residues that are required for EBOV entry. Defining the TIM IgV residues needed for EBOV entry clarifies the virus-receptor interactions and paves the way for the development of novel therapeutics targeting virus binding to this cell surface receptor. Ebolavirus and Marburgvirus, members of the Filoviridae family, are enveloped, negative-sense RNA viruses that cause severe hemorrhagic fever in humans and nonhuman primates. A member of the Ebolavirus genus, Ebola virus (EBOV), is a causative agent of episodic filovirus outbreaks in Africa, including the most recent and deadly West African epidemic that began in December 2013 (1, 2). Contributing to the virulent nature of this virus is the ...

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“…Kim-1 is known to directly interact with phosphatidylinositol-3-kinase (PI3K) pathway subunit p85 and regulate PI3K signaling in a phosphotyrosinedependent manner. 42 Recently, we demonstrated that Kim-1 interaction with p85 and subsequent PI3K-dependent signaling pathway play an important role in kidney injury and repair. 37,43 The PI3K/AKT/mTOR pathway is a well known intracellular signaling pathway related to cell growth, proliferation, and survival.…”

Section: Discussionmentioning

confidence: 99%

Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model

Yin¹,

Naini²,

Chen³

et al. 2015

JASN

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Kidney injury molecule 1 (KIM-1), an epithelial phagocytic receptor, is markedly upregulated in the proximal tubule in various forms of acute and chronic kidney injury in humans and many other species. Whereas acute expression of KIM-1 has adaptive anti-inflammatory effects, chronic expression may be maladaptive in mice. Here, we characterized the zebrafish Kim family, consisting of Kim-1, Kim-3, and Kim-4. Kim-1 was markedly upregulated in kidney after gentamicin-induced injury and had conserved phagocytic activity in zebrafish. Both constitutive and tamoxifen-induced expression of Kim-1 in zebrafish kidney tubules resulted in loss of the tubule brush border, reduced GFR, pericardial edema, and increased mortality. Kim-1-induced kidney injury was associated with reduction of growth of adult fish. Kim-1 expression led to activation of the mammalian target of rapamycin (mTOR) pathway, and inhibition of this pathway with rapamycin increased survival. mTOR pathway inhibition in KIM-1-overexpressing transgenic mice also significantly ameliorated serum creatinine level, proteinuria, tubular injury, and kidney inflammation. In conclusion, persistent Kim-1 expression results in chronic kidney damage in zebrafish through a mechanism involving mTOR. This observation predicted the role of the mTOR pathway and the therapeutic efficacy of mTOR-targeted agents in KIM-1-mediated kidney injury and fibrosis in mice, demonstrating the utility of the Kim-1 renal tubule zebrafish models.

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

Cited by 62 publications

References 43 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

Characterization of Human and Murine T-Cell Immunoglobulin Mucin Domain 4 (TIM-4) IgV Domain Residues Critical for Ebola Virus Entry

Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model

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