Tec Family Kinases in T Lymphocyte Development and Function

Berg, Leslie J.; Finkelstein, Lisa D.; Lucas, Julie Ann; Schwartzberg, Pamela L.

doi:10.1146/annurev.immunol.22.012703.104743

Cited by 293 publications

(362 citation statements)

References 211 publications

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“…The role of Tec family kinases in conventional ␣␤ T cell development, differentiation, and function has been well documented (33)(34)(35). Of the three family members expressed in T cells, Itk, Rlk, and Tec, Itk has the predominant role in TCR-dependent thymic selection events, as well as in TCR-dependent activation of mature T cells.…”

Section: Discussionmentioning

confidence: 99%

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The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

Felices

Berg

2008

The Journal of Immunology

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105

125

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The Tec kinases Itk and Rlk are required for efficient positive selection of conventional CD4+ and CD8+ T cells in the thymus. In contrast, recent studies have shown that these Tec kinases are dispensable for the development of CD8+ T cells with characteristics of innate T cells. These findings raise questions about the potential role of Itk and Rlk in NKT cell development, because NKT cells represent a subset of innate T cells. To address this issue, we examined invariant NKT cells in Itk−/− and Itk/Rlk−/− mice. We find, as has been reported previously, that Itk−/− mice have reduced numbers of NKT cells with a predominantly immature phenotype. We further show that this defect is greatly exacerbated in the absence of both Itk and Rlk, leading to a 7-fold reduction in invariant NKT cell numbers in the thymus of Itk/Rlk−/− mice and a more severe block in NKT cell maturation. Splenic Itk−/− and Itk/Rlk−/− NKT cells are also functionally defective, because they produce little to no cytokine following in vivo activation. Tec kinase-deficient NKT cells also show enhanced cell death in the spleen. These defects correlate with greatly diminished expression of CD122, the IL-2R/IL-15R β-chain, and impaired expression of the T-box transcription factor, T-bet. These data indicate that the Tec kinases Itk and Rlk provide important signals for terminal maturation, efficient cytokine production, and peripheral survival of NKT cells.

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Section: Discussionmentioning

confidence: 99%

“…The Tec family of nonreceptor tyrosine kinases has been shown to play a significant role in signaling downstream of the TCR (33,34). Three members of this family are expressed in conventional ␣␤TCR ϩ T cells, as follows: Itk, Rlk, and Tec.…”

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confidence: 99%

The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

Felices

Berg

2008

The Journal of Immunology

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105

125

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“…Studies have demonstrated that one likely candidate that may be responsible for T cell hyporesponsiveness is the Tec family kinase Tec [89]. IL-12 treatment of CD4 + T cells in peripheral blood has been shown to increase the expression of the Tec kinases [90]. Studies in vivo have also demonstrated that IL-12 can enhance synapse formation and unresponsive T cells once treated with IL-12 were able to respond to weak peptides or self peptides [91].…”

Section: Role Of Interleukin-12 In Til Hyporesponsivenessmentioning

confidence: 99%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

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“…Mice with a deletion in the tec kinase ITK have reduced numbers of both peripheral CD4 ϩ and CD8 ϩ T cells (15). Among the CD8 ϩ T cells that are present, the majority express high levels of CD44 and CD122 (16).…”

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confidence: 99%

ITK and IL-15 support two distinct subsets of CD8⁺T cells

Dubois

Waldmann

Müller

2006

Proc. Natl. Acad. Sci. U.S.A.

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(3,4). In addition, IL-15 Ϫ/Ϫ mice are unable to maintain antigen-specific CD8 ϩ memory T cells after immunization with viruses (5, 6). These defects point to functions of IL-15 in both adaptive and innate immunity.Antigenic stimulation of naïve CD8 ϩ T cells induces the high expression of CD44 (7,8), for which all CD44 hi CD8 ϩ T cells were termed ''memory phenotype'' cells. An injection of IL-15 into mice induces the expansion of these CD8 ϩ CD44 hi T cells independent of antigenic stimulation (9, 10). It was concluded that IL-15 directly supports the maintenance of CD8 ϩ memory T cells. However, a number of other treatments also selectively increase the number of CD8 ϩ CD44 hi T cells without antigenic stimulation that include ''bystander'' proliferation in response to poly I:C or LPS (11), proliferation after an injection of mature dendritic cells (12), or lymphopenia-induced proliferation after CD8 ϩ T cell transfer into irradiated hosts (13,14). Because the presence of antigen should be a necessity for the generation of true memory cells, subsets of CD8 ϩ CD44 hi T cells may have functions other than in CD8 memory.Mice with a deletion in the tec kinase ITK have reduced numbers of both peripheral CD4 ϩ and CD8 ϩ T cells (15). Among the CD8 ϩ T cells that are present, the majority express high levels of CD44 and CD122 (16). The function of these cells has not been fully elucidated. Defects in CD8 ϩ T cells in ITK Ϫ/Ϫ mice include positive and negative selection, cytokine production, TCR engagement-induced proliferation, and reduced cytolytic activity against allogenic splenocytes and against virally infected cells (15).Here we show that IL-15 and ITK support two distinct subsets of CD8 ϩ T cells that are present in both the thymus and the periphery. The two subpopulations of CD8 ϩ T cells appear to have independent functions in the periphery. ResultsCD8 ؉ T Cells in ITK ؊/؊ Mice Depend on IL-15. CD8 ϩ T cells in ITK Ϫ/Ϫ mice and in IL-15 Ϫ/Ϫ mice are phenotypically different. In particular, CD8 ϩ T cells in ITK Ϫ/Ϫ mice express high levels of CD44 and CD122. In contrast, IL-15 Ϫ/Ϫ CD8 ϩ T cells express low levels of CD44 and CD122. This difference could be caused by a dysregulation of both surface markers. Alternatively, ITK and IL-15 could support two distinct subsets of CD8 ϩ T cells. To distinguish between these possibilities, we determined whether the CD44 hi CD122 hi CD8 ϩ T cells in ITK Ϫ/Ϫ mice depend on IL-15. We initially injected the antibody ⌻m␤1, which inhibits the activity of transpresented IL-15 on the IL-2͞15R␤ chain. One week after a 50-g injection of ⌻m␤1, the percentage of peripheral blood CD8 ϩ T cells in ITK Ϫ/Ϫ mice was reduced to Ͻ15% compared with untreated wild-type mice (Fig. 1A). All of the remaining CD8 ϩ T cells expressed high levels of CD44 and CD122 ( Fig. 1 A and data not shown).We then generated mice that are deficient in both ITK and IL-15. CD8 ϩ CD44 hi CD122 hi T cells represent 10-30% of all CD8 ϩ T cells in young wild-type mice. As described previously (3) and as shown i...

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Tec Family Kinases in T Lymphocyte Development and Function

Cited by 293 publications

References 211 publications

The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

ITK and IL-15 support two distinct subsets of CD8⁺T cells

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Tec Family Kinases in T Lymphocyte Development and Function

Cited by 293 publications

References 211 publications

The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

ITK and IL-15 support two distinct subsets of CD8+T cells

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ITK and IL-15 support two distinct subsets of CD8⁺T cells