Self-Antigen Maintains the Innate Antibacterial Function of Self-Specific CD8 T Cells In Vivo

Dhanji, Salim; Chow, Michael; Teh, Hung‐Sia

doi:10.4049/jimmunol.177.1.138

Cited by 16 publications

(24 citation statements)

References 53 publications

(61 reference statements)

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“…To explain the contrasting functions of these memory phenotype CD8 ϩ T cells that exhibit both innate functions and suppressive functions, we propose differential conditions used to activate memory phenotype CD8 T cells from either wildtype or RasGRP Ϫ/Ϫ mice lead to distinct immunological functions. The development of memory phenotype CD8 T cells in RasGRP1 Ϫ/Ϫ mice may be due to high affinity TCR interactions with self Ags, because we have previously demonstrated the high expression levels of the memory markers CD44 and CD122 found in naive mice are maintained when the self Ag is present (43,44). These studies complement those conducted in Itk Ϫ/Ϫ and Itk Ϫ/Ϫ Rlk Ϫ/Ϫ mice and support the hypothesis that unconventional CD8 T cells differ from conventional CD8 T cells in the requirement for Itk, Rlk, and RasGRP1 for their development.…”

Section: Discussionmentioning

confidence: 99%

Preferential Development of CD4 and CD8 T Regulatory Cells in RasGRP1-Deficient Mice

Chen

Priatel

Chow

et al. 2008

The Journal of Immunology

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RasGRP1 and Sos are two Ras-guanyl-nucleotide exchange factors that link TCR signal transduction to Ras and MAPK activation. Recent studies demonstrate positive selection of developing thymocytes is crucially dependent on RasGRP1, whereas negative selection of autoreactive thymocytes appears to be RasGRP1 independent. However, the role of RasGRP1 in T regulatory (Treg) cell development and function is unknown. In this study, we characterized the development and function of CD4+CD25+Foxp3+ and CD8+CD44highCD122+ Treg lineages in RasGRP1−/− mice. Despite impaired CD4 Treg cell development in the thymus, the periphery of RasGRP1−/− mice contained significantly increased frequencies of CD4+Foxp3+ Treg cells that possessed a more activated cell surface phenotype. Furthermore, on a per cell basis, CD4+Foxp3+ Treg cells from mutant mice are more suppressive than their wild-type counterparts. Our data also suggest that the lymphopenic environment in the mutant mice plays a dominant role of favored peripheral development of CD4 Treg cells. These studies suggest that whereas RasGRP1 is crucial for the intrathymic development of CD4 Treg cells, it is not required for their peripheral expansion and function. By contrast to CD4+CD25+Foxp3+ T cells, intrathymic development of CD8+CD44highCD122+ Treg cells is unaffected by the RasGRP1−/− mutation. Moreover, RasGRP1−/− mice contained greater numbers of CD8+CD44highCD122+ T cells in the spleen, relative to wild-type mice. Activated CD8 Treg cells from RasGRP1−/− mice retained their ability to synthesize IL-10 and suppress the proliferation of wild-type CD8+CD122− T cells, albeit at a much lower efficiency than wild-type CD8 Treg cells.

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Section: Discussionmentioning

confidence: 99%

Preferential Development of CD4 and CD8 T Regulatory Cells in RasGRP1-Deficient Mice

Chen

Priatel

Chow

et al. 2008

The Journal of Immunology

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“…This has been most clearly demonstrated in a Listeria monocytogenes system, in which innate CD8 + T cells produce high levels of IFN-γ as bystander T cells, and thereby reduce bacterial titers at the peak of the infection (39). Bystander CD8 + T cells have also been shown to up-regulate Eomes and to acquire effector functions during virus infections in a response that was dependent on weak TCR interactions and cytokines, in this case, type I IFNs; this latter response was particularly striking because it occurred in >70% of the bystander T cells (30).…”

Section: Peripheral Cd8 + T Cells In Irf4mentioning

confidence: 99%

TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8 ⁺ T-cell differentiation

Nayar

Enos

Prince

et al. 2012

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

113

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CD8 + T-cell development in the thymus generates a predominant population of conventional naive cells, along with minor populations of “innate” T cells that resemble memory cells. Recent studies analyzing a variety of KO or knock-in mice have indicated that impairments in the T-cell receptor (TCR) signaling pathway produce increased numbers of innate CD8 + T cells, characterized by their high expression of CD44, CD122, CXCR3, and the transcription factor, Eomesodermin (Eomes). One component of this altered development is a non-CD8 + T cell-intrinsic role for IL-4. To determine whether reduced TCR signaling within the CD8 + T cells might also contribute to this pathway, we investigated the role of the transcription factor, IFN regulatory factor 4 (IRF4). IRF4 is up-regulated following TCR stimulation in WT T cells; further, this up-regulation is impaired in T cells treated with a small-molecule inhibitor of the Tec family tyrosine kinase, IL-2 inducible T-cell kinase (ITK). In contrast to WT cells, activation of IRF4-deficient CD8 + T cells leads to rapid and robust expression of Eomes, which is further enhanced by IL-4 stimulation. In addition, inhibition of ITK together with IL-4 increases Eomeso up-regulation. These data indicate that ITK signaling promotes IRF4 up-regulation following CD8 + T-cell activation and that this signaling pathway normally suppresses Eomes expression, thereby regulating the differentiation pathway of CD8 + T cells.

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“…Recently, a population of CD8 + T cells with "innate" like function expressing a similar memory-like phenotype has been identified [15,16]. These cells are CD8 + CD44…”

Section: Introductionmentioning

confidence: 99%

Memory phenotype CD8⁺ T cells with innate function selectively develop in the absence of active Itk

Sahu

Walsh

et al. 2007

Eur J Immunol

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T cells with a memory-like phenotype and possessing innate immune function have been previously identified as CD8(+)CD44(hi) cells. These cells rapidly secrete IFN-gamma upon stimulation with IL-12/IL-18 and are involved in innate responses to infection with Listeria monocytogenes. The signals regulating these cells are unclear. The Tec kinase Itk regulates T cell activation and we report here that a majority of the CD8(+) T cells in Itk null mice have a phenotype of CD44(hi) similar to memory-like innate T cells. These cells are observed in mice carrying an Itk mutant lacking the kinase domain, indicating that active Tec kinase signaling suppresses their presence. These cells carry preformed message for and are able to rapidly produce IFN-gamma upon stimulation in vitro with IL-12/IL-18, and endow Itk null mice the ability to effectively respond to infection with L. monocytogenes or exposure to lipopolysaccharides by secretion of IFN-gamma. Transfer of these cells rescues the ability of IFN-gamma null mice to reduce bacterial burden following L. monocytogenes infection, indicating that these cells are functional CD8(+)CD44(hi) T cells previously detected in vivo. These results indicate that active signals from Tec kinases regulate the development of memory-like CD8(+) T cells with innate function.

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Self-Antigen Maintains the Innate Antibacterial Function of Self-Specific CD8 T Cells In Vivo

Cited by 16 publications

References 53 publications

Preferential Development of CD4 and CD8 T Regulatory Cells in RasGRP1-Deficient Mice

Preferential Development of CD4 and CD8 T Regulatory Cells in RasGRP1-Deficient Mice

TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8 ⁺ T-cell differentiation

Memory phenotype CD8⁺ T cells with innate function selectively develop in the absence of active Itk

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Self-Antigen Maintains the Innate Antibacterial Function of Self-Specific CD8 T Cells In Vivo

Cited by 16 publications

References 53 publications

Preferential Development of CD4 and CD8 T Regulatory Cells in RasGRP1-Deficient Mice

Preferential Development of CD4 and CD8 T Regulatory Cells in RasGRP1-Deficient Mice

TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8 + T-cell differentiation

Memory phenotype CD8+ T cells with innate function selectively develop in the absence of active Itk

Contact Info

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TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8 ⁺ T-cell differentiation

Memory phenotype CD8⁺ T cells with innate function selectively develop in the absence of active Itk