scholarly journals Delayed protection by ESAT-6–specific effector CD4+ T cells after airborne M. tuberculosis infection

2008 ◽  
Vol 205 (10) ◽  
pp. 2359-2368 ◽  
Author(s):  
Alena M. Gallegos ◽  
Eric G. Pamer ◽  
Michael S. Glickman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Tuberculosis Infection ◽  
Th1 Cells ◽  
Mycobacterium Tuberculosis Infection ◽  
Immunodominant Antigen ◽  
Specific Effector ◽  
Aerosol Infection

Mycobacterium tuberculosis infection induces complex CD4 T cell responses that include T helper type 1 (Th1) cells and regulatory T cells. Although Th1 cells control infection, they are unable to fully eliminate M. tuberculosis, suggesting that Th1-mediated immunity is restrained from its full sterilizing potential. Investigation into T cell–mediated defense is hindered by difficulties in expanding M. tuberculosis–specific T cells. To circumvent this problem, we cloned CD4+ T cells from M. tuberculosis–infected B6 mice and generated transgenic mice expressing a T cell receptor specific for the immunodominant antigen early secreted antigenic target 6 (ESAT-6). Adoptively transferred naive ESAT-6–specific CD4+ T cells are activated in pulmonary lymph nodes between 7 and 10 d after aerosol infection and undergo robust expansion before trafficking to the lung. Adoptive transfer of activated ESAT-6–specific Th1 cells into naive recipients before aerosol M. tuberculosis infection dramatically enhances resistance, resulting in 100-fold fewer bacteria in infected lungs. However, despite large numbers of Th1 cells in the lungs of mice at the time of M. tuberculosis challenge, protection was not manifested until after 7 d following infection. Our results demonstrate that pathogen-specific Th1 cells can provide protection against inhaled M. tuberculosis, but only after the first week of infection.

Mycobacterium tuberculosis Rv3615c is a highly immunodominant antigen and specifically induces potent Th1-type immune responses in tuberculosis pleurisy

2017 ◽  
Vol 131 (15) ◽  
pp. 1859-1876 ◽  
Author(s):  
Jiangping Li ◽  
Juan Shen ◽  
Suihua Lao ◽  
Xiaomin Li ◽  
Jie Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd4 T Cells ◽  
Specific Antigen ◽  
T Cell Responses ◽  
Tuberculosis Infection ◽  
Effector Memory ◽  
Cell Responses ◽  
Immunodominant Antigen

T-cell responses have been demonstrated to be essential for preventing Mycobacterium tuberculosis infection. The Th1-cytokines produced by T cells, such as INF-γ, IL-2, and TNF-α, not only limit the invasion of M. tuberculosis but also eliminate the pathogen at the site of infection. Bacillus Calmette–Guérin (BCG) is known to induce Th1-type responses but the protection is inadequate. Identification of immunogenic components, in addition to those expressed in BCG, and induction of a broad spectrum of Th1-type responses provide options for generating sufficient adaptive immunity. Here, we studied human pulmonary T-cell responses induced by the M. tuberculosis-specific antigen Rv3615c, a protein with a similar size and sequence homology to ESAT-6 and CFP-10, which induced dominant CD4+ T-cell responses in human tuberculosis (TB) models. We characterized T-cell responses including cytokine profiling, kinetics of activation, expansion, differentiation, TCR usage, and signaling of activation induced by Rv3615c compared with other M. tuberculosis-specific antigens. The expanded CD4+ T cells induced by Rv3615c predominately produced Th1, but less Th2 and Th17, cytokines and displayed effector/memory phenotypes (CD45RO+CD27−CD127−CCR7−). The magnitude of expansion and cytokine production was comparable to those induced by well-characterized the 6 kDa early secreted antigenic target (ESAT-6), the 10 kDa culture filtrate protein (CFP-10) and BCG. Rv3615c contained multiple epitopes Rv3615c1–15, Rv3615c6–20, Rv3615c66–80, Rv3615c71–85 and Rv3615c76–90 that activated CD4+ T cells. The Rv3615c-specific CD4+ T cells shared biased of T-cell receptor variable region of β chain (TCR Vβ) 1, 2, 4, 5.1, 7.1, 7.2 and/or 22 chains to promote their differentiation and proliferation respectively, by triggering a signaling cascade. Our data suggest that Rv3615c is a major target of Th1-type responses and can be a highly immunodominant antigen specific for M. tuberculosis infection.

scholarly journals Ceramide Synthase 2 Null Mice Are Protected from Ovalbumin-Induced Asthma with Higher T Cell Receptor Signal Strength in CD4+ T Cells

2021 ◽  
Vol 22 (5) ◽  
pp. 2713
Author(s):  
Sun-Hye Shin ◽  
Kyung-Ah Cho ◽  
Hee-Soo Yoon ◽  
So-Yeon Kim ◽  
Hee-Yeon Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Acyl Chain ◽  
Signal Strength ◽  
Cell Receptor ◽  
Ceramide Synthase ◽  
Asthmatic Patients

(1) Background: six mammalian ceramide synthases (CerS1–6) determine the acyl chain length of sphingolipids (SLs). Although ceramide levels are increased in murine allergic asthma models and in asthmatic patients, the precise role of SLs with specific chain lengths is still unclear. The role of CerS2, which mainly synthesizes C22–C24 ceramides, was investigated in immune responses elicited by airway inflammation using CerS2 null mice. (2) Methods: asthma was induced in wild type (WT) and CerS2 null mice with ovalbumin (OVA), and inflammatory cytokines and CD4 (cluster of differentiation 4)+ T helper (Th) cell profiles were analyzed. We also compared the functional capacity of CD4+ T cells isolated from WT and CerS2 null mice. (3) Results: CerS2 null mice exhibited milder symptoms and lower Th2 responses than WT mice after OVA exposure. CerS2 null CD4+ T cells showed impaired Th2 and increased Th17 responses with concomitant higher T cell receptor (TCR) signal strength after TCR stimulation. Notably, increased Th17 responses of CerS2 null CD4+ T cells appeared only in TCR-mediated, but not in TCR-independent, treatment. (4) Conclusions: altered Th2/Th17 immune response with higher TCR signal strength was observed in CerS2 null CD4+ T cells upon TCR stimulation. CerS2 and very-long chain SLs may be therapeutic targets for Th2-related diseases such as asthma.

scholarly journals Cutting Edge: Control of Mycobacterium tuberculosis Infection by a Subset of Lung Parenchyma–Homing CD4 T Cells

2014 ◽  
Vol 192 (7) ◽  
pp. 2965-2969 ◽  
Author(s):  
Shunsuke Sakai ◽  
Keith D. Kauffman ◽  
Jason M. Schenkel ◽  
Cortez C. McBerry ◽  
Katrin D. Mayer-Barber ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Cd4 T Cells ◽  
Lung Parenchyma ◽  
Cutting Edge ◽  
Tuberculosis Infection ◽  
Mycobacterium Tuberculosis Infection

scholarly journals Functional Uncoupling of T-cell Receptor Engagement and Lck Activation in Anergic Human Thymic CD4+T Cells

2001 ◽  
Vol 276 (20) ◽  
pp. 17455-17460 ◽  
Author(s):  
Wakae Fujimaki ◽  
Makio Iwashima ◽  
Junji Yagi ◽  
Hua Zhang ◽  
Hisako Yagi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor

scholarly journals Multifunctional CD4+ T cells correlate with active Mycobacterium tuberculosis infection

2010 ◽  
Vol 40 (8) ◽  
pp. 2211-2220 ◽  
Author(s):  
Nadia Caccamo ◽  
Giuliana Guggino ◽  
Simone A. Joosten ◽  
Giuseppe Gelsomino ◽  
Paola Di Carlo ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Cd4 T Cells ◽  
Tuberculosis Infection ◽  
Mycobacterium Tuberculosis Infection

scholarly journals CD4+ T Cells from Glutamic Acid Decarboxylase (GAD)65-specific T Cell Receptor Transgenic Mice Are Not Diabetogenic and Can Delay Diabetes Transfer

2002 ◽  
Vol 196 (4) ◽  
pp. 481-492 ◽  
Author(s):  
Kristin V. Tarbell ◽  
Mark Lee ◽  
Erik Ranheim ◽  
Cheng Chi Chao ◽  
Maija Sanna ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
T Cell Receptor ◽  
Glutamic Acid Decarboxylase ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Acid Decarboxylase ◽  
Gad 65

Glutamic acid decarboxylase (GAD)65 is an early and important antigen in both human diabetes mellitus and the nonobese diabetic (NOD) mouse. However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear. T cell responses to GAD65 occur early in diabetes pathogenesis, yet only one GAD65-specific T cell clone of many identified can transfer diabetes. We have generated transgenic mice on the NOD background expressing a T cell receptor (TCR)-specific for peptide epitope 286–300 (p286) of GAD65. These mice have GAD65-specific CD4+ T cells, as shown by staining with an I-Ag7(p286) tetramer reagent. Lymphocytes from these TCR transgenic mice proliferate and make interferon γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α, and IL-10 when stimulated in vitro with GAD65 peptide 286–300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable. Furthermore, in vitro activated CD4 T cells from GAD 286 TCR transgenic mice express higher levels of CTL-associated antigen (CTLA)-4 than nontransgenic littermates. CD4+ T cells, or p286-tetramer+CD4+ Tcells, from GAD65 286–300-specific TCR transgenic mice delay diabetes induced in NOD.scid mice by diabetic NOD spleen cells. This data suggests that GAD65 peptide 286–300-specific T cells have disease protective capacity and are not pathogenic.

scholarly journals CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 580-588 ◽  
Author(s):  
Kathrin Gollmer ◽  
François Asperti-Boursin ◽  
Yoshihiko Tanaka ◽  
Klaus Okkenhaug ◽  
Bart Vanhaesebroeck ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Early Time ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Activation Markers

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.

T-CELL RECEPTOR INDEPENDENT ACTIVATION OF CD4+T-CELLS IN SEVERE ACUTE PANCREATITIS

Pancreas ◽  
2008 ◽  
Vol 37 (4) ◽  
pp. 468
Author(s):  
A. Dummer ◽  
M. Sendler ◽  
F.-U. Weiss ◽  
B. M. Bröker ◽  
M. M. Lerch ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Pancreatitis ◽  
T Cell ◽  
T Cell Receptor ◽  
Severe Acute Pancreatitis ◽  
Cd4 T Cells ◽  
Cell Receptor

scholarly journals Human CD4+ T cells specific for dominant epitopes of SARS-CoV-2 Spike and Nucleocapsid proteins with therapeutic potential

2021 ◽  
Author(s):  
Johan Verhagen ◽  
Edith Van der Meijden ◽  
Vanessa Lang ◽  
Andreas Kremer ◽  
Simon Völkl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cd4 T Cells ◽  
Cellular Therapy ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Haematopoietic Stem Cell ◽  
T Cell Therapy ◽  
Immunological Protection

Since December 2019, Coronavirus disease-19 (COVID-19) has spread rapidly across the world, leading to a global effort to develop vaccines and treatments. Despite extensive progress, there remains a need for treatments to bolster the immune responses in infected immunocompromised individuals, such as cancer patients who recently underwent a haematopoietic stem cell transplantation. Immunological protection against COVID-19 is mediated by both short-lived neutralising antibodies and long-lasting virus-reactive T cells. Therefore, we propose that T cell therapy may augment efficacy of current treatments. For the greatest efficacy with minimal adverse effects, it is important that any cellular therapy is designed to be as specific and directed as possible. Here, we identify T cells from COVID-19 patients with a potentially protective response to two major antigens of the SARS-CoV-2 virus, Spike and Nucleocapsid protein. By generating clones of highly virus-reactive CD4+ T cells, we were able to confirm a set of 9 immunodominant epitopes and characterise T cell responses against these. Accordingly, the sensitivity of T cell clones for their specific epitope, as well as the extent and focus of their cytokine response was examined. Moreover, by using an advanced T cell receptor (TCR) sequencing approach, we determined the paired TCR sequences of clones of interest. While these data on a limited population require further expansion for universal application, the results presented here form a crucial first step towards TCR-transgenic CD4+ T cell therapy of COVID-19.

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