scholarly journals The requirements for natural Th17 cell development are distinct from those of conventional Th17 cells

2011 ◽  
Vol 208 (11) ◽  
pp. 2201-2207 ◽  
Author(s):  
Jiyeon S. Kim ◽  
Jennifer E. Smith-Garvin ◽  
Gary A. Koretzky ◽  
Martha S. Jordan
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Critical Role ◽  
Adaptive Immune Response ◽  
Cell Receptor ◽  
Class Ii ◽  
T Helper 17 ◽  
Differential Signaling

CD4+ T helper 17 (Th17) cells play a critical role in the adaptive immune response against extracellular pathogens. Most studies to date have focused on understanding the differentiation of Th17 cells from naive CD4+ T cells in peripheral effector sites. However, Th17 cells are present in the thymus. In this study, we demonstrate that a population of Th17 cells, natural Th17 cells (nTh17 cells), which acquire effector function during development in the thymus before peripheral antigen exposure, shows preferential usage of T cell receptor Vβ3. nTh17 cells are dependent on major histocompatibility complex (MHC) class II for thymic selection, yet unlike conventional CD4+ T cells, MHC class II expression on thymic cortical epithelium is not sufficient for their development, rather expression on medullary epithelium is necessary. Differential signaling requirements for IL-17 priming further distinguish nTh17 from conventional Th17 cells. Collectively, our findings define a Th17 population, poised to rapidly produce cytokines, that is developmentally distinct from conventional Th17 cells and that potentially functions at the interface of innate and adaptive immunity.

A T Cell Receptor Signaling Mutant Reveals Two Distinct Populations of IL-17 Producing CD4+ T Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 186-186
Author(s):  
Jiyeon S Kim ◽  
Jennifer E Smith-Garvin ◽  
Martha S Jordan ◽  
Gary A Koretzky
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Critical Role ◽  
Cell Receptor ◽  
Class Ii ◽  
Interleukin 17

Abstract Abstract 186 Interleukin-17 (IL-17) producing CD4+ T cells (Th17 cells) are essential for immune responses in mucosal and epithelial sites which are the first line of host defense. Th17 cells play a critical role in the pathogenesis of many inflammatory and autoimmune diseases, and the role of IL-17 and Th17 cells in cancer has recently become the focus of extensive investigation. Most studies to date have focused on elucidating the cell extrinsic requirements for differentiation of Th17 cells from naïve CD4+ T cells in peripheral effector sites. Here we report an unconventional population of Th17 cells, “natural Th17 cells” (nTh17), that acquire effector function during development in the thymus, thereby distinguishing them from conventional Th17 cells which require antigen encounter and differentiation in the periphery. We show that these nTh17 cells are present and indeed develop in the thymus using fetal thymic organ culture. nTh17 cells express surface markers consistent with an innate and/or activated phenotype and their development is dependent on selection by MHC class II in the thymus. Yet unlike conventional CD4+ T cells, MHC class II expression on thymic cortical epithelium is not sufficient for their development, rather expression on medullary epithelium is necessary. In addition, T cell receptor (TCR) repertoire analysis of nTh17 cells revealed unique characteristics in TCR gene usage compared to conventional Th17 cells. A mouse model with a mutation in the TCR signaling protein SLP76 (SLP76 Y145F mice) further highlights the difference between the two distinct Th17 populations. SLP76 Y145F mice have increased numbers of nTh17 cells in the thymus compared to wild-type mice. However, peripheral naïve CD4+ T cells from these mice showed severely defective IL-17 production when cultured in vitro under conditions promoting Th17 cell differentiation. This defect was reflected in vivo as CD4+ T cells in the small intestinal lamina propria of SLP76 Y145F mice fail to produce IL-17. Using mixed radiation bone marrow chimeras, we found that the aberrant Th17 phenotype in the thymus and periphery of SLP76 Y145F mice is cell-intrinsic. Finally, adoptive transfer of purified nTh17 cells into RAG-deficient host mice revealed preferential homing of nTh17 cells to thymus and lung compared to other comparison/competitive populations that were co-transferred. Taken together, our data suggest a distinct population of Th17 cells that have characteristics of innate lymphocytes that function at the interface between innate and adaptive immunity. Understanding the biology of nTh17 cells will provide insight into the recently identified Th17 cells in human thymi and umbilical cord blood. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Engineering CD4+ T Cells to Enhance Cancer Immunity

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1721 ◽  
Author(s):  
Francesca Sillito ◽  
Angelika Holler ◽  
Hans J. Stauss
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Cytotoxic T Cells ◽  
Critical Role ◽  
Cell Receptor ◽  
Convincing Evidence ◽  
Indirect Pathway ◽  
Tumour Immunity

This review presents key advances in combining T cell receptor (TCR) gene transfer to redirect T-cell specificity with gene engineering in order to enhance cancer-protective immune function. We discuss how emerging insights might be applied to CD4+ T cells. Although much attention has been paid to the role of CD8+ cytotoxic T cells in tumour protection, we provide convincing evidence that CD4+ helper T cells play a critical role in cancer immune responses in animal models and also in patients. We demonstrate that genetic engineering technologies provide exciting opportunities to extend the specificity range of CD4+ T cells from MHC class-II-presented epitopes to include peptides presented by MHC class I molecules. Functional enhancement of tumour immunity can improve the sensitivity of T cells to cancer antigens, promote survival in a hostile tumour microenvironment, boost cancer-protective effector mechanisms and enable the formation of T-cell memory. Engineered cancer-specific CD4+ T cells may contribute to protective immunity by a direct pathway involving cancer cell killing, and by an indirect pathway that boosts the function, persistence and memory formation of CD8+ T cells.

scholarly journals Amino acid residues that flank core peptide epitopes and the extracellular domains of CD4 modulate differential signaling through the T cell receptor.

1994 ◽  
Vol 179 (6) ◽  
pp. 1945-1956 ◽  
Author(s):  
D A Vignali ◽  
J L Strominger
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Class Ii ◽  
Peptide Epitopes ◽  
Differential Signaling ◽  
Effective Signal

Hen egg lysozyme 52-61-specific CD4+ T cells responded by interleukin 2 (IL-2) secretion to any peptide containing this epitope regardless of length of NH2- and COOH-terminal composition. However, CD4- variants could only respond to peptides containing the two COOH-terminal tryptophans at positions 62 and 63. Substitutions at these positions defined patterns of reactivity that were specific for individual T cells inferring a T cell receptor (TCR)-based phenomenon. Thus, the fine specificity of major histocompatibility complex (MHC)-peptide recognition by the TCR was dramatically affected by CD4 and the COOH-terminal peptide composition. Peptides that failed to induce IL-2 secretion in the CD4- variants nevertheless induced strong tyrosine phosphorylation of CD3 zeta. Thus, whereas the TCR still recognized and bound to the MHC class II-peptide complex resulting in protein phosphorylation, this interaction failed to induce effective signal transduction manifested by IL-2 secretion. This provides a clear example of differential signaling mediated by peptides known to be naturally processed. In addition, the external domains of CD4, rather than its cytoplasmic tail, were critical in aiding TCR recognition of all peptides derived from a single epitope. These data suggest that the nested flanking residues, which are present on MHC class II but not class I bound peptides, are functionally relevant.

Developmental dissociation of T cells from B, NK, and myeloid cells revealed by MHC class II–specific chimeric immune receptors bearing TCR-ζ or FcR-γ chain signaling domains

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 3045-3048 ◽  
Author(s):  
Wei Yu Lin ◽  
Margo R. Roberts
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Critical Role ◽  
Cell Receptor ◽  
Class Ii ◽  
Hematopoietic Stem ◽  
Retroviral Transduction ◽  
Immune Receptors ◽  
Signaling Domain ◽  
Signaling Domains

The T-cell receptor ζ (TCR-ζ) and FcR-γ chains play a critical role in mediating signal transduction. We have previously described HIV glycoprotein 120 (gp120)–specific chimeric immune receptors (CIRs) in which the extracellular domain of CD4 is linked to the signaling domain of ζ (CD4ζ) or γ (CD4γ). Such CIRs are efficiently expressed following retroviral transduction of mature T cells and specifically redirect effector functions toward HIV-infected targets. In this report, we examine development of CD4ζ- or CD4γ-expressing T cells from retrovirally transduced hematopoietic stem cells following bone marrow transplantation. Although CD4ζ/γ-expressing myeloid, NK, and B cells were efficiently reconstituted, parallel development of CD4ζ/γ-expressing T cells was blocked prior to the CD25+CD44+prothymocyte stage. In contrast, T cells expressing a signaling-defective CIR were efficiently generated. When major histocompatibility complex (MHC) class II–deficient mice were used as transplant recipients, development of CD4ζ/γ-expressing T cells was restored. We conclude that CD4ζ/γ signaling generated following engagement of MHC class II selectively arrests T-lineage development.

scholarly journals Generation of PLZF+ CD4+ T cells via MHC class II–dependent thymocyte–thymocyte interaction is a physiological process in humans

2009 ◽  
Vol 207 (1) ◽  
pp. 237-246 ◽  
Author(s):  
You Jeong Lee ◽  
Yoon Kyung Jeon ◽  
Byung Hyun Kang ◽  
Doo Hyun Chung ◽  
Chung-Gyu Park ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Zinc Finger Protein ◽  
Cell Subset ◽  
Cell Receptor ◽  
Class Ii ◽  
Inkt Cells ◽  
Mhc Class Ii Molecules

Human thymocytes, unlike mouse thymocytes, express major histocompatibility complex (MHC) class II molecules on their surface, especially during the fetal and perinatal stages. Based on this observation, we previously identified a novel developmental pathway for the generation of CD4+ T cells via interactions between MHC class II–expressing thymocytes (thymocyte–thymocyte [T–T] interactions) with a transgenic mouse system. However, the developmental dissection of this T–T interaction in humans has not been possible because of the lack of known cellular molecules specific for T–T CD4+ T cells. We show that promyelocytic leukemia zinc finger protein (PLZF) is a useful marker for the identification of T–T CD4+ T cells. With this analysis, we determined that a substantial number of fetal thymocytes and splenocytes express PLZF and acquire innate characteristics during their development in humans. Although these characteristics are quite similar to invariant NKT (iNKT) cells, they clearly differ from iNKT cells in that they have a diverse T cell receptor repertoire and are restricted by MHC class II molecules. These findings define a novel human CD4+ T cell subset that develops via an MHC class II–dependent T–T interaction.

scholarly journals The Class II Phosphatidylinositol 3 kinase C2β Is Required for the Activation of the K+ Channel KCa3.1 and CD4 T-Cells

2009 ◽  
Vol 20 (17) ◽  
pp. 3783-3791 ◽  
Author(s):  
Shekhar Srivastava ◽  
Lie Di ◽  
Olga Zhdanova ◽  
Zhai Li ◽  
Santosha Vardhana ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Class Ii ◽  
K Channel ◽  
Channel Activity ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

The Ca2+-activated K+ channel KCa3.1 is required for Ca2+ influx and the subsequent activation of T-cells. We previously showed that nucleoside diphosphate kinase beta (NDPK-B), a mammalian histidine kinase, directly phosphorylates and activates KCa3.1 and is required for the activation of human CD4 T lymphocytes. We now show that the class II phosphatidylinositol 3 kinase C2β (PI3K-C2β) is activated by the T-cell receptor (TCR) and functions upstream of NDPK-B to activate KCa3.1 channel activity. Decreased expression of PI3K-C2β by siRNA in human CD4 T-cells resulted in inhibition of KCa3.1 channel activity. The inhibition was due to decreased phosphatidylinositol 3-phosphate [PI(3)P] because dialyzing PI3K-C2β siRNA-treated T-cells with PI(3)P rescued KCa3.1 channel activity. Moreover, overexpression of PI3K-C2β in KCa3.1-transfected Jurkat T-cells led to increased TCR-stimulated activation of KCa3.1 and Ca2+ influx, whereas silencing of PI3K-C2β inhibited both responses. Using total internal reflection fluorescence microscopy and planar lipid bilayers, we found that PI3K-C2β colocalized with Zap70 and the TCR in peripheral microclusters in the immunological synapse. This is the first demonstration that a class II PI3K plays a critical role in T-cell activation.

Analysis Of Circulating Rhinovirus-Specific CD4+ T Cells Using Novel MHC Class II Tetramers Reveals Marked Expansion Of Effector Memory Cells In Infected Subjects

2014 ◽  
Vol 133 (2) ◽  
pp. AB292
Author(s):  
Lyndsey Muehling ◽  
Rachana Agrawal ◽  
Julia Wisniewski ◽  
Paul Wright ◽  
William W. Kwok ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Effector Memory ◽  
Memory Cells ◽  
Effector Memory Cells

scholarly journals Murine myeloproliferative disorder as a consequence of impaired collaboration between dendritic cells and CD4 T cells

Blood ◽  
2019 ◽  
Vol 133 (4) ◽  
pp. 319-330 ◽  
Author(s):  
Stéphanie Humblet-Baron ◽  
John S. Barber ◽  
Carlos P. Roca ◽  
Aurelie Lenaerts ◽  
Pandelakis A. Koni ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Adaptive Immune Response ◽  
Extramedullary Hematopoiesis ◽  
Myeloproliferative Disorder ◽  
Myeloid Differentiation ◽  
Normal Numbers ◽  
Congenital Deficiency

Abstract Dendritic cells (DCs) are a key cell type in the initiation of the adaptive immune response. Recently, an additional role for DCs in suppressing myeloproliferation was discovered. Myeloproliferative disorder (MPD) was observed in murine studies with constitutive depletion of DCs, as well as in patients with congenital deficiency in DCs caused by mutations in GATA2 or IRF8. The mechanistic link between DC deficiency and MPD was not predicted through the known biology and has remained an enigma. Prevailing models suggest numerical DC deficiency leads to MPD through compensatory myeloid differentiation. Here, we formally tested whether MPD can also arise through a loss of DC function without numerical deficiency. Using mice whose DCs are deficient in antigen presentation, we find spontaneous MPD that is characterized by splenomegaly, neutrophilia, and extramedullary hematopoiesis, despite normal numbers of DCs. Disease development was dependent on loss of the MHC class II (MHCII) antigen-presenting complex on DCs and was eliminated in mice deficient in total lymphocytes. Mice lacking MHCII and CD4 T cells did not develop disease. Thus, MPD was paradoxically contingent on the presence of CD4 T cells and on a failure of DCs to activate CD4 T cells, trapping the cells in a naive Flt3 ligand–expressing state. These results identify a novel requirement for intercellular collaboration between DCs and CD4 T cells to regulate myeloid differentiation. Our findings support a new conceptual framework of DC biology in preventing MPD in mice and humans.

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