Rapid effector function of circulating CD4+ T cells specific for immunodominant regions of the conserved serine/threonine kinase found in Streptococcus pneumoniae (StkP) in healthy adults

ABSTRACT In the Streptococcus pneumoniae genome, stkP, encoding a membrane-associated serine/threonine kinase, is not redundant (L. Novakova, S. Romao, J. Echenique, P. Branny, and M.-C. Trombe, unpublished results). The data presented here demonstrate that StkP belongs to the signaling network involved in competence triggering in vitro and lung infection and bloodstream invasion in vivo. In competence, functional StkP is required for activation of comCDE upstream of the autoregulated ring orchestrated by the competence-stimulating peptide. This is the first description of positive regulation of comCDE transcription in balance with its repression by CiaRH.

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Cutting Edge: Itk-Dependent Signals Required for CD4+ T Cells to Exert, but Not Gain, Th2 Effector Function

The Journal of Immunology ◽

10.4049/jimmunol.176.7.3895 ◽

2006 ◽

Vol 176 (7) ◽

pp. 3895-3899 ◽

Cited By ~ 47

Author(s):

Byron B. Au-Yeung ◽

Shoshana D. Katzman ◽

Deborah J. Fowell

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Effector Function ◽

Cutting Edge

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CARMA1 Is Required for Akt-Mediated NF-κB Activation in T Cells

Molecular and Cellular Biology ◽

10.1128/mcb.26.6.2327-2336.2006 ◽

2006 ◽

Vol 26 (6) ◽

pp. 2327-2336 ◽

Cited By ~ 57

Author(s):

Preeti Narayan ◽

Brittany Holt ◽

Richard Tosti ◽

Lawrence P. Kane

Keyword(s):

T Cells ◽

T Cell ◽

Cell Receptor ◽

Functional Interaction ◽

Serine Threonine Kinase ◽

Threonine Kinase ◽

Kinase C ◽

Evolutionarily Conserved ◽

The Common ◽

Protein Kinase C Activation

ABSTRACT Many details of the generic pathway for induction of NF-κB have been delineated, but it is still not clear how multiple, diverse receptor systems are able to converge on this evolutionarily conserved family of transcription factors. Recent studies have shown that the CARMA1, Bcl10, and MALT1 proteins are critical for coupling the common elements of the NF-κB pathway to the T-cell receptor (TCR) and CD28. We previously demonstrated a role for the serine/threonine kinase Akt in CD28-mediated NF-κB induction. Using a CARMA1-deficient T-cell line, we have now found that the CARMA complex is required for induction of NF-κB by Akt, in cooperation with protein kinase C activation. Furthermore, using a novel selective inhibitor of Akt, we confirm that Akt plays a modulatory role in NF-κB induction by the TCR and CD28. Finally, we provide evidence for a physical and functional interaction between Akt and CARMA and for Akt-dependent phosphorylation of Bcl10. Therefore, in T cells, Akt impinges upon NF-κB signaling through at least two separate mechanisms.

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Accessory cells control induction of CD4+ T cells with specific effector function

Research in Immunology ◽

10.1016/0923-2494(91)90012-8 ◽

1991 ◽

Vol 142 (1) ◽

pp. 50-54 ◽

Cited By ~ 3

Author(s):

S.A. Stohlman

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Effector Function ◽

Accessory Cells ◽

Specific Effector

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Deregulated Expression of Immune Checkpoints on Circulating CD4 T Cells May Complicate Clinical Outcome and Response to Treatment with Checkpoint Inhibitors in Multiple Myeloma Patients

International Journal of Molecular Sciences ◽

10.3390/ijms22179298 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9298

Author(s):

Anna Kulikowska de Nałęcz ◽

Lidia Ciszak ◽

Lidia Usnarska-Zubkiewicz ◽

Irena Frydecka ◽

Edyta Pawlak ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Checkpoint Inhibitors ◽

Effector Function ◽

Response To Treatment ◽

Immune Checkpoints ◽

Effective Control ◽

Small Subset

Unlike solid-tumor patients, a disappointingly small subset of multiple myeloma (MM) patients treated with checkpoint inhibitors derive clinical benefits, suggesting differential participation of inhibitory receptors involved in the development of T-cell-mediated immunosuppression. In fact, T cells in MM patients have recently been shown to display features of immunosenescence and exhaustion involved in immune response inhibition. Therefore, we aimed to identify the dominant inhibitory pathway in MM patients to achieve its effective control by therapeutic interventions. By flow cytometry, we examined peripheral blood (PB) CD4 T cell characteristics assigned to senescence or exhaustion, considering PD-1, CTLA-4, and BTLA checkpoint expression, as well as secretory effector function, i.e., capacity for IFN-γ and IL-17 secretion. Analyses were performed in a total of 40 active myeloma patients (newly diagnosed and treated) and 20 healthy controls. At the single-cell level, we found a loss of studied checkpoints’ expression on MM CD4 T cells (both effector (Teff) and regulatory (Treg) cells) primarily at diagnosis; the checkpoint deficit in MM relapse was not significant. Nonetheless, PD-1 was the only checkpoint distributed on an increased proportion of T cells in all MM patients irrespective of disease phase, and its expression on CD4 Teff cells correlated with adverse clinical courses. Among patients, the relative defect in secretory effector function of CD4 T cells was more pronounced at myeloma relapse (as seen in declined Th1/Treg and Th17/Treg cell rates). Although the contribution of PD-1 to MM clinical outcomes is suggestive, our study clearly indicated that the inappropriate expression of immune checkpoints (associated with dysfunctionality of CD4 T cells and disease clinical phase) might be responsible for the sub-optimal clinical response to therapeutic checkpoint inhibitors in MM.

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Thymic selection pathway regulates the effector function of CD4 T cells

Journal of Experimental Medicine ◽

10.1084/jem.20070321 ◽

2007 ◽

Vol 204 (9) ◽

pp. 2145-2157 ◽

Cited By ~ 39

Author(s):

Wei Li ◽

M. Hanief Sofi ◽

Norman Yeh ◽

Sarita Sehra ◽

Brian P. McCarthy ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Mrna Level ◽

Cell Receptor ◽

Effector Function ◽

Thymic Selection ◽

Th2 Cytokines ◽

Independent Manner

Recently, a new developmental pathway for CD4 T cells that is mediated by major histocompatibility complex class II–positive thymocytes was identified (Choi, E.Y., K.C. Jung, H.J. Park, D.H. Chung, J.S. Song, S.D. Yang, E. Simpson, and S.H. Park. 2005. Immunity. 23:387–396; Li, W., M.G. Kim, T.S. Gourley, B.P. McCarthy, D.B. Sant'angelo, and C.H. Chang. 2005. Immunity. 23:375–386). We demonstrate that thymocyte-selected CD4 (T-CD4) T cells can rapidly produce interferon γ and interleukin (IL) 4 upon in vivo and in vitro T cell receptor stimulation. These T-CD4 T cells appear to be effector cells producing both T helper type 1 (Th1) and Th2 cytokines, and they maintain a potential to produce Th2 cytokines under Th1-skewing conditions in a signal transducer and activator of transcription 6–independent manner. The IL-4 mRNA level is high in CD4 single-positive thymocytes if they are selected on thymocytes, which is at least partly caused by enhanced histone acetylation of the IL-4 locus. However, mice that can generate T-CD4 T cells showed attenuated immune responses in an allergen-induced airway inflammation model, suggesting a protective role for T-CD4 T cells during an airway challenge. Our results imply that this thymic selection pathway plays an important role in determining the effector function of the resulting CD4 cells and in regulating immune response.

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