Impairment in a negative regulatory system for TCR signaling in CD4+T cells from old mice

Abstract CD4+ T cells use the chemokine receptor CCR7 to home to and migrate within lymphoid tissue, where T-cell activation takes place. Using primary T-cell receptor (TCR)–transgenic (tg) CD4+ T cells, we explored the effect of CCR7 ligands, in particular CCL21, on T-cell activation. We found that the presence of CCL21 during early time points strongly increased in vitro T-cell proliferation after TCR stimulation, correlating with increased expression of early activation markers. CCL21 costimulation resulted in increased Ras- and Rac-GTP formation and enhanced phosphorylation of Akt, MEK, and ERK but not p38 or JNK. Kinase-dead PI3KδD910A/D910A or PI3Kγ-deficient TCR-tg CD4+ T cells showed similar responsiveness to CCL21 costimulation as control CD4+ T cells. Conversely, deficiency in the Rac guanine exchange factor DOCK2 significantly impaired CCL21-mediated costimulation in TCR-tg CD4+ T cells, concomitant with impaired Rac- but not Ras-GTP formation. Using lymph node slices for live monitoring of T-cell behavior and activation, we found that G protein-coupled receptor signaling was required for early CD69 expression but not for Ca2+ signaling. Our data suggest that the presence of CCL21 during early TCR signaling lowers the activation threshold through Ras- and Rac-dependent pathways leading to increased ERK phosphorylation.

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HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4+CD8+ thymocytes for CD4-lineage commitment

eLife ◽

10.7554/elife.43821 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 3

Author(s):

Rachael Laura Philips ◽

Jeong-Heon Lee ◽

Krutika Gaonkar ◽

Pritha Chanana ◽

Ji Young Chung ◽

...

Keyword(s):

T Cells ◽

Mhc Class Ii ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Lineage Commitment ◽

Cytokine Signaling ◽

Rna Seq ◽

Kinetics Analysis ◽

Tcr Signaling ◽

Histone Deacetylase 3

CD4 and CD8 T cells are vital components of the immune system. We found that histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as HDAC3-deficient DP thymocytes generate only CD8SP thymocytes in mice. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage, which occurs with accelerated kinetics. Analysis of histone acetylation and RNA-seq reveals that HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection. Commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. Despite elevated IL-21R/γc/STAT5 signaling in HDAC3-deficient DP thymocytes, blocking IL-21R does not restore CD4 lineage commitment. Instead, HDAC3 binds directly to CD8-lineage promoting genes. Thus, HDAC3 is required to restrain CD8-lineage genes in DP thymocytes for the generation of CD4 T cells.

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The FcRγ Subunit and Syk Kinase Replace the CD3ζ-Chain and ZAP-70 Kinase in the TCR Signaling Complex of Human Effector CD4 T Cells

The Journal of Immunology ◽

10.4049/jimmunol.170.8.4189 ◽

2003 ◽

Vol 170 (8) ◽

pp. 4189-4195 ◽

Cited By ~ 88

Author(s):

Sandeep Krishnan ◽

Vishal G. Warke ◽

Madhusoodana P. Nambiar ◽

George C. Tsokos ◽

Donna L. Farber

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Tcr Signaling ◽

Signaling Complex ◽

Syk Kinase

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Exposure of Human CD4 T Cells to IL-12 Results in Enhanced TCR-Induced Cytokine Production, Altered TCR Signaling, and Increased Oxidative Metabolism

PLoS ONE ◽

10.1371/journal.pone.0157175 ◽

2016 ◽

Vol 11 (6) ◽

pp. e0157175 ◽

Cited By ~ 15

Author(s):

Aldo Vacaflores ◽

Nicole M. Chapman ◽

John T. Harty ◽

Martin J. Richer ◽

Jon C. D. Houtman

Keyword(s):

T Cells ◽

Oxidative Metabolism ◽

Cd4 T Cells ◽

Cytokine Production ◽

Tcr Signaling

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Self-recognition drives the preferential accumulation of promiscuous CD4+ T-cells in aged mice

eLife ◽

10.7554/elife.05949 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 19

Author(s):

Neha R Deshpande ◽

Heather L Parrish ◽

Michael S Kuhns

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cell Biology ◽

Fold Increase ◽

Cell Receptor ◽

Cd4 T Cell ◽

Fundamental Aspect ◽

Cell Compartment ◽

Old Mice

T-cell recognition of self and foreign peptide antigens presented in major histocompatibility complex molecules (pMHC) is essential for life-long immunity. How the ability of the CD4+ T-cell compartment to bind self- and foreign-pMHC changes over the lifespan remains a fundamental aspect of T-cell biology that is largely unexplored. We report that, while old mice (18–22 months) contain fewer CD4+ T-cells compared with adults (8–12 weeks), those that remain have a higher intrinsic affinity for self-pMHC, as measured by CD5 expression. Old mice also have more cells that bind individual or multiple distinct foreign-pMHCs, and the fold increase in pMHC-binding populations is directly related to their CD5 levels. These data demonstrate that the CD4+ T-cell compartment preferentially accumulates promiscuous constituents with age as a consequence of higher affinity T-cell receptor interactions with self-pMHC.

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Adaptive Immune Responses Mediated Age-related Plasmodium yoelii 17XL and 17XNL Infections in 4 and 8-week-old BALB/c Mice

10.21203/rs.2.15639/v1 ◽

2019 ◽

Author(s):

Qiu-bo Wang ◽

Yun-ting Du ◽

Fei Liu ◽

Xiao-dan Sun ◽

Xun Sun ◽

...

Keyword(s):

T Cells ◽

Survival Rate ◽

Cd4 T Cells ◽

Plasmodium Yoelii ◽

Th2 Cells ◽

Dependent Manner ◽

Adaptive Immune ◽

Age Related ◽

Ifn Γ ◽

Old Mice

Abstract Background As the quest to eradicate malaria continues, it is important to clarify the opposite clinical outcomes between childhood and adulthood. The relationship between adaptive immune response and age-related malaria infection remains unknown. Methods 4 and 8-week-old mice were used to mimic childhood and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-special IgG were measured by ELISA. Results Infant mice were more susceptible to P. yoelii 17XNL infection, with lower survival rate and higher parasitemia. The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4 + T-bet + IFN-γ + Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4 + GATA3 + IL-4 + Th2 cells and CD4 + CXCR5 + Tfh cells, and IL-4 production in the 8-week-old mice obviously increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-special IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4 + or activated CD4 + T cells in the 8-week-old mice as compared to the 4-week-old group. Conclusion We consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4 + T cells exhaustion.

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Lineage-specific Requirement for Signal Transducer and Activator of Transcription (Stat)4 in Interferon γ Production from CD4+ Versus CD8+ T Cells

Journal of Experimental Medicine ◽

10.1084/jem.189.8.1355 ◽

1999 ◽

Vol 189 (8) ◽

pp. 1355-1360 ◽

Cited By ~ 130

Author(s):

Laura L. Carter ◽

Kenneth M. Murphy

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Interferon Γ ◽

Cytolytic Activity ◽

Signal Transducer ◽

Specific Requirement ◽

Tcr Signaling ◽

Effector Functions ◽

Ifn Γ

CD4+ and CD8+ T cells exhibit important differences in their major effector functions. CD8+ T cells provide protection against pathogens through cytolytic activity, whereas CD4+ T cells exert important regulatory activity through production of cytokines. However, both lineages can produce interferon (IFN)-γ, which can contribute to protective immunity. Here we show that CD4+ and CD8+ T cells differ in their regulation of IFN-γ production. Both lineages require signal transducer and activator of transcription (Stat)4 activation for IFN-γ induced by interleukin (IL)-12/IL-18 signaling, but only CD4+ T cells require Stat4 for IFN-γ induction via the TCR pathway. In response to antigen, CD8+ T cells can produce IFN-γ independently of IL-12, whereas CD4+ T cells require IL-12 and Stat4 activation. Thus, there is a lineage-specific requirement for Stat4 activation in antigen-induced IFN-γ production based on differences in TCR signaling between CD4+ and CD8+ T cells.

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TCR Signaling Antagonizes Rapid IP-10-Mediated Transendothelial Migration of Effector Memory CD4+ T Cells

The Journal of Immunology ◽

10.4049/jimmunol.178.5.3237 ◽

2007 ◽

Vol 178 (5) ◽

pp. 3237-3243 ◽

Cited By ~ 23

Author(s):

Thomas D. Manes ◽

Stephen L. Shiao ◽

Thomas J. Dengler ◽

Jordan S. Pober

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Transendothelial Migration ◽

Effector Memory ◽

Tcr Signaling ◽

Memory Cd4 T Cells

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CD95 Expression in Aged Mice Infected with Tuberculosis

Infection and Immunity ◽

10.1128/iai.66.10.5036-5040.1998 ◽

1998 ◽

Vol 66 (10) ◽

pp. 5036-5040 ◽

Cited By ~ 5

Author(s):

A. D. Roberts ◽

Ian M. Orme

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

Cd4 T Cells ◽

Activated T Cells ◽

Homeostatic Mechanism ◽

Aged Mice ◽

Induction Of Apoptosis ◽

Old Mice

ABSTRACT The interaction between CD95 and its ligand is an important homeostatic mechanism that leads to the induction of apoptosis in activated T cells. In view of recent evidence that this pathway might be defective in aged mice, this study investigated CD95 expression on T cells in old mice activated by infection with Mycobacterium tuberculosis. The results of the study do not support the hypothesis that CD95 is poorly expressed on CD4 T cells from old mice; instead, it was found that similar numbers of T cells from young and old mice expressed CD95, with the intensity of expression if anything higher on the cells from the old mice. In addition, the study demonstrated that changes in CD44 and CD45RB expression previously observed in young infected mice proceeded in a similar fashion in old animals and, as would be predicted, that CD95hi expression was primarily associated with CD4 T cells expressing the activated CD44hi CD45RBhi phenotype.

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