Role of acid sphingomyelinase bioactivity in human CD4+ T-cell activation and immune responses

Background: Despite the well-established association between T cell-mediated inflammation and non-ischemic heart failure (HF), the specific mechanisms triggering T cell activation during the progression of HF and the antigens involved are poorly understood. We hypothesized that myocardial oxidative stress induces the formation of isolevuglandin (IsoLG)-modified proteins that function as cardiac neoantigens to elicit CD4+ T cell receptor (TCR) activation and promote HF. Methods: We used transverse aortic constriction (TAC) in mice to trigger myocardial oxidative stress and T cell infiltration. We profiled the TCR repertoire by mRNA sequencing of intramyocardial activated CD4+ T cells in Nur77 GFP reporter mice, which transiently express GFP upon TCR engagement. We assessed the role of antigen presentation and TCR specificity in the development of cardiac dysfunction using antigen presentation-deficient MhcII -/- mice, and TCR transgenic OTII mice that lack specificity for endogenous antigens. We detected IsoLG-protein adducts in failing human hearts. We also evaluated the role of reactive oxygen species (ROS) and IsoLGs in eliciting T cell immune responses in vivo by treating mice with the antioxidant TEMPOL, and the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) during TAC, and ex-vivo in mechanistic studies of CD4+ T cell proliferation in response to IsoLG-modified cardiac proteins. Results: We discovered that TCR antigen recognition increases in the left ventricle (LV) as cardiac dysfunction progresses, and identified a limited repertoire of activated CD4+ T cell clonotypes in the LV. Antigen presentation of endogenous antigens was required to develop cardiac dysfunction since MhcII -/- mice reconstituted with CD4+ T cells, and OTII mice immunized with their cognate antigen were protected from TAC-induced cardiac dysfunction despite the presence of LV-infiltrated CD4+ T cells. Scavenging IsoLGs with 2-HOBA reduced TCR activation and prevented cardiac dysfunction. Mechanistically, cardiac pressure overload resulted in ROS dependent dendritic cell accumulation of IsoLG-protein adducts which induced robust CD4+ T cell proliferation. Conclusions: Collectively, our study demonstrates an important role of ROS-induced formation of IsoLG-modified cardiac neoantigens that lead to TCR-dependent CD4+ T cell activation within the heart.

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HIV-specific T-cell Responses and Generalized Activation in HIV-1 Infected Long-term Non-progressors and Progressors from South India

Current HIV Research ◽

10.2174/1570162x17666181212122607 ◽

2019 ◽

Vol 16 (4) ◽

pp. 302-314

Author(s):

Chinnambedu Ravichandran Swathirajan ◽

Ramachandran Vignesh ◽

Greer Waldrop ◽

Uma Shanmugasundaram ◽

Pannerselvam Nandagopal ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cd4 T Cell ◽

Cell Responses ◽

Activation Rates ◽

Hiv 1

Background:Anti-viral cytokine expressions by cytotoxic T-cells and lower activation rates have been reported to correlate with suppressed HIV replication in long-term non-progressors (LTNP). Immune mechanisms underlying disease non-progression in LTNP might vary with HIV-1 subtype and geographical locations.Objective:This study evaluates cytokine expression and T-cells activation in relation to disease non-progression in LTNP.Methods:HIV-1 Subtype C infected LTNP (n=20) and progressors (n=15) were enrolled and flowcytometry assays were performed to study HIV-specific CD8 T-cells expressing IL-2, IFN-γ, TNF-α and MIP-1β against gag and env peptides. CD4+ T-cell activation was evaluated by surface expression of HLADR and CD38.Results:Proportions of cytokines studied did not differ significantly between LTNP and progressors, while contrasting correlations with disease progression markers were observed in LTNP. CD4+ T-cell activation rates were significantly lower in LTNP compared to progressors which indicate the potential role of T-cell activation rates in disease non-progression in LTNP.Conclusion:LTNP and progressors showed similar CD8+ T-cell responses, but final conclusions can be drawn only by comparing multiple immune factors in larger LTNP cohort with HIV-1 infected individuals at various levels of disease progression. A possible role of HIV-1 subtype variation and ethnic differences in addition to host-genetic and viral factors cannot be ruled out.

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The role of PIM kinases in human and mouse CD4+ T cell activation and inflammatory bowel disease

Cellular Immunology ◽

10.1016/j.cellimm.2011.10.011 ◽

2012 ◽

Vol 272 (2) ◽

pp. 200-213 ◽

Cited By ~ 25

Author(s):

Leila J. Jackson ◽

Jed A. Pheneger ◽

Tracy J. Pheneger ◽

Gregg Davis ◽

A. Dale Wright ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

T Cell ◽

T Cell Activation ◽

Bowel Disease ◽

Cell Activation ◽

Cd4 T Cell ◽

Pim Kinases ◽

Inflammatory Bowel ◽

Human And Mouse

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RAFTsomes Containing Epitope-MHC-II Complexes Mediated CD4+ T Cell Activation and Antigen-Specific Immune Responses

Pharmaceutical Research ◽

10.1007/s11095-012-0849-7 ◽

2012 ◽

Vol 30 (1) ◽

pp. 60-69 ◽

Cited By ~ 19

Author(s):

Qian Ding ◽

Jian Chen ◽

Xiaohui Wei ◽

Wenqiang Sun ◽

Junhua Mai ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Cd4 T Cell ◽

Mhc Ii

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CD47 Regulates Red Blood Cell Alloimmunization in Mice

Blood ◽

10.1182/blood-2019-131598 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 100-100

Author(s):

Ryan Jajosky ◽

Connie Arthur ◽

Jerry Allen ◽

Megan Fuller ◽

Patricia E Zerra ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Response ◽

Cell Activation ◽

T Cell Response ◽

Cell Uptake ◽

Cd4 T Cell ◽

Flow Cytometric ◽

Rbc Transfusion

Background: Exposure to red blood cell (RBC) alloantigens during pregnancy or transfusion can lead to the development of alloantibodies and result in transfusion-related complications, including hemolytic transfusion reactions and hemolytic disease of the fetus and newborn. However, the factors that regulate RBC alloimmunization remain incompletely understood. Several studies suggest that alterations in factors that regulate RBC clearance may impact RBC uptake and antigen presentation, directly influencing the likelihood of RBC alloimmunization. To test this, we directly examined the potential role of CD47, a master regulator of RBC removal previously shown to be altered during RBC senescence and cold storage. To accomplish this, we crossed transgenic mice that express the model HOD antigen (a fusion protein consisting of hen egg lysozyme fused to ovalbumin and human Duffy b) with CD47 knock out (KO) mice to generate HOD RBC donors with wild type, heterozygous or homozygous KO levels of CD47 and used these donors to define the impact of CD47 on antibody formation following RBC transfusion. Methods: HOD transgenic mice expressing the HOD antigen exclusively on RBCs were crossed with CD47-/- mice to produce HOD CD47+/- or HOD CD47-/- mice. HOD and CD47 levels were assessed by flow cytometric analysis using anti-HOD and anti-CD47 antibodies. HOD CD47+/+, HOD CD47+/- or HOD CD47-/- RBCs were transfused into C57BL6 recipients, followed by serum collection on days 14 and 28 post transfusion and evaluation of anti-HOD antibodies by flow cytometry crossmatch. To determine the CD4 T cell response to transfusion, TCR transgenics specific to ovalbumin (OTII) were labeled with CFSE, followed by adoptive transfer, transfusion of HOD CD47+/+, HOD CD47+/- or HOD CD47-/- RBCs and evaluation of T cell proliferation, activation and cytokine secretion. Cellular removal of HOD RBCs was determined by flow cytometric examination of CFSE-labeled HOD RBCs. Finally, antigen levels on HOD RBCs was determined by staining cells with anti-HEL antibodies followed by flow cytometric examination. All three groups were subjected to one-way ANOVA analysis with a p value <0.05 considered significant. Results: While HOD CD47+/+ RBCs expressed levels of CD47 comparable to WT RBCs, HOD CD47+/- RBCs exhibited significantly reduced CD47 levels (nearly half that observed on WT HOD RBCs) and HOD CD47-/-RBCs failed to express any detectable CD47 (p < 0.0001). Following transfusion, HOD CD47+/- and HOD CD47-/- RBCs produced significantly higher levels of IgG anti-HOD antibodies than HOD CD47+/+ RBCs on days 14 and 28 post-transfusion (p < 0.001). However, while HOD CD47-/- RBCs displayed increased clearance consistent with the possible enhancement of a CD4 T cell response (p < 0.0001), HOD CD47+/- RBCs failed to exhibit any different in clearance when compared to HOD CD47+/+ RBCs overtime. To examine the potential impact of differences in HOD RBC clearance on CD4 T cell activation, OTII T cell proliferation was evaluated. While HOD CD47-/- RBC transfusion resulted in significantly increased 33D1+ dendritic cell uptake, OTII proliferation, activation and cytokine secretion (p < 0.05), no difference in 33D1+ dendritic cell uptake or T cell response was observed following HOD CD47+/+ RBC or HOD CD47+/- RBC transfusion. Instead, HOD CD47+/- RBCs exhibited enhanced antigen removal, while also displaying an increased ability to activate HEL specific B cells when compared to HOD CD47+/+ or HOD CD47-/- RBC transfusion. Conclusions: These results demonstrate that alterations in CD47, which occur during normal RBC senescence and cold storage, directly influence RBC alloimmunization through different mechanisms depending on the extent of CD47 loss. While complete loss of CD47 results in enhanced RBC clearance, antigen presentation and CD4 T cell activation, reductions in CD47 to half WT levels failed to impact RBC clearance or T cell activation, but instead enhanced antigen specific B cell activation. These results demonstrate that even partial loss of CD47 is capable of significantly enhancing alloantibody formation completely independent of its role in regulating RBC clearance. In doing so, these findings provide novel insight into the role of CD47 as a key regulator of RBC alloimmunization. Disclosures Stowell: Grifols: Honoraria.

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Adoptive Immune Responses to Sars-Cov2 Vaccination in CART19 Treated Patients

Blood ◽

10.1182/blood-2021-153730 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1757-1757

Author(s):

Kalpana Parvathaneni ◽

Kyabeth Toress-Rodriguez ◽

Wenzhao Meng ◽

James Knox ◽

Xiaoming Xu ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Board Of Directors ◽

T Cell Activation ◽

Research Funding ◽

Cell Activation ◽

Cd4 T Cell ◽

Advisory Committees ◽

Cell Immunity ◽

T Cell Immune Responses

Abstract Abstract Background: The two FDA approved mRNA-based SARS-CoV2 vaccines have shown >90% efficacy at preventing COVID and eliciting protective immunity in nearly all healthy individuals. However, the extent of vaccine induced antibody and T cell immunity in immunocompromised patients is not well known. Our study objective is to determine if patients with hematologic malignancies treated with B-cell targeting chimeric antigen receptor (CAR) T cell therapies can mount antibody and T cell immune responses to SARS-CoV2 vaccines. A prospective single-center study to evaluate the SARS-CoV2 immune responses in immunocompromised individuals (COVAX Study) was initiated at University of Pennsylvania following the IRB guidelines. The study enrolled 8 healthy adults,12 patients are in remission after treatment (average of 40.6 months) with CART cells targeting either CD19 or CD19+CD22 and received both doses of SARS-CoV2 vaccine. Methods and Results: Serology to SARS-CoV2 spike-receptor binding domain (RBD) IgG, RBD-IgA, RBD-IgM and spike-specific T cell responses were measured prior to vaccination and serially up to 28 days after booster vaccination. RBD-IgG and RBD-IgA were detected in 8/8 and 7/8 healthy subjects compared to 5/12 and 2/12 CART patients, respectively (Figure A). In the CART cohort, several patients who demonstrated an induction of RBD-IgG (57.2/uL +/- 20.2) compared to those who were RBD-IgG-negative (9/uL +/- 10.1, ANOVA with multiple comparisons test p=0.017) have higher level of circulating B cells. No association was found with time since CART infusion, age, disease type, or vaccine manufacturer. All 8 healthy subjects demonstrated induction of SARS-Cov2 spike-specific CD4 + T cell immunity compared to 7 out of 11 CART patients (Figure B). RBD-IgG responses were not correlated with CD4 + T cell activation (Pearson correlation, R=0.21, p=0.53). Indeed, 3 CART patients demonstrated robust CD4 + T cell activation despite absence of antibody induction. Overall, 8/12 CART patients demonstrated induction of either or both humoral and T cell immune responses. Conclusions: We show that immune responses to SARS-CoV2 mRNA vaccines are induced in majority of patients who have been treated with CART therapies targeting B-cell lineage antigens. Induction of vaccine-specific antibody was strongly associated with the level of circulating B cells. However, in CART cohort patients despite severe humoral immune deficiency, strong CD4 + T cell responses were observed suggestive of a sufficient protective immunity. Figure 1 Figure 1. Disclosures Frey: Novartis: Research Funding; Sana Biotechnology: Consultancy; Kite Pharma: Consultancy; Syndax Pharmaceuticals: Consultancy. Garfall: Amgen: Honoraria; CRISPR Therapeutics: Research Funding; GlaxoSmithKline: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Research Funding; Tmunity: Research Funding. Porter: American Society for Transplantation and Cellular Therapy: Honoraria; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; ASH: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity: Patents & Royalties; Wiley and Sons Publishing: Honoraria. June: AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy; Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company; Novartis: Patents & Royalties.

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Innate and Adaptive Immune Responses Both Contribute to Pathological CD4 T Cell Activation in HIV-1 Infected Ugandans

PLoS ONE ◽

10.1371/journal.pone.0018779 ◽

2011 ◽

Vol 6 (4) ◽

pp. e18779 ◽

Cited By ~ 31

Author(s):

Michael A. Eller ◽

Kim G. Blom ◽

Veronica D. Gonzalez ◽

Leigh Anne Eller ◽

Prossy Naluyima ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Cd4 T Cell ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Hiv 1

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Antigen targeting to splenic CD169+ macrophages induces strong humoral immune responses and CD4+ T cell activation

Molecular Immunology ◽

10.1016/j.molimm.2012.02.030 ◽

2012 ◽

Vol 51 (1) ◽

pp. 12-13

Author(s):

Henrike Veninga ◽

Ellen Borg ◽

Hakan Kalay ◽

Yvette van Kooyk ◽

Georg Kraal ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Cd4 T Cell ◽

Humoral Immune ◽

Humoral Immune Responses

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Genomic profiling of T cell activation reveals dependency of memory T cells on CD28 costimulation

10.1101/421099 ◽

2018 ◽

Cited By ~ 3

Author(s):

Dafni A. Glinos ◽

Blagoje Soskic ◽

Luke Jostins ◽

David M. Sansom ◽

Gosia Trynka

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Memory T Cells ◽

Cd4 T Cell ◽

Genomic Profiling ◽

Memory Cells ◽

Cell Responses

SummaryT cell activation is a critical driver of immune response and if uncontrolled, it can result in failure to respond to infection or in excessive inflammation and autoimmunity. CD28 costimulatory pathway is an essential regulator of CD4 T cell responses. To deconvolute how T cell receptor (TCR) and CD28 orchestrate activation of human CD4 T cells we stimulated cells using varying intensities of TCR and CD28 signals followed by gene expression profiling. We demonstrate that T-helper differentiation and cytokine expression are controlled by CD28. Strikingly, cell cycle and cell division are sensitive to CD28 in memory cells, but under TCR control in naive cells, in contrast to the paradigm that memory cells are CD28-independent. Using a combination of chromatin accessibility and enhancer profiling, we observe that IRFs and Blimp-1 (PRDM1) motifs are enriched in naive and memory T cells in response to TCR. In contrast, memory cells initiate AP1 transcriptional regulation only when both TCR and CD28 are engaged, implicating CD28 as an amplifier of transcriptional programmes in memory cells. Lastly, we show that CD28-sensitive genes are enriched in autoimmune disease loci, pointing towards the role of memory cells and the regulation of T cell activation through CD28 in autoimmune disease development. This study provides important insights into the differential role of CD28 in naive and memory T cell responses and offers a new platform for design and interpretation of costimulatory based therapies.One-sentence summaryGenomic profiling of CD4 T cell activation reveals a sensitivity switch from TCR in naive to CD28 in memory cells.

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