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MAdCAM-1 Costimulates T Cells Through Integrin Alpha4/Beta7 to Cause Gene Expression Events Resembling Costimulation Through CD28

ABSTRACT: After revealing no effect of vedolizumab upon T cell density in colon biopsies, we demonstrate that MAdCAM-1 delivers a costimulatory signal comparable to that of CD28 in T cells both functionally and at the gene expression level, with only subtle differences identified in the latter concerning cytokines involved in pyogenic inflammation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196026 | GEO | 2022/02/11

REPOSITORIES: GEO

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MAdCAM-1 Costimulates T Cells Through Integrin Alpha4/Beta7 to Cause Gene Expression Events Resembling Costimulation Through CD28

Project description:MAdCAM-1 Costimulates T Cells Through Integrin Alpha4/Beta7 to Cause Gene Expression Events Resembling Costimulation Through CD28

| PRJNA803039 | ENA

MAdCAM costimulation through Integrin-α4β7 promotes HIV replication.

Project description:Human gut-associated lymphoid tissues (GALT) play a key role in the acute phase of HIV infection. The propensity of HIV to replicate in these tissues, however, is not fully understood. Access and migration of naive and memory CD4+ T cells to these sites is mediated by interactions between integrin α4β7, expressed on CD4+ T cells, and MAdCAM, expressed on high endothelial venules. We report here that MAdCAM delivers a potent costimulatory signal to naive and memory CD4+ T cells following ligation with α4β7. Such costimulation promotes high levels of HIV replication. An anti-α4β7 mAb that prevents mucosal transmission of SIV blocks MAdCAM signaling through α4β7 and MAdCAM-dependent viral replication. MAdCAM costimulation of memory CD4+ T cells is sufficient to drive cellular proliferation and the upregulation of CCR5, while naive CD4+ T cells require both MAdCAM and retinoic acid to achieve the same response. The pairing of MAdCAM and retinoic acid is unique to the GALT, leading us to propose that HIV replication in these sites is facilitated by MAdCAM-α4β7 interactions. Moreover, complete inhibition of MAdCAM signaling by an anti-α4β7 mAb, an analog of the clinically approved therapeutic vedolizumab, highlights the potential of such agents to control acute HIV infection.

| S-EPMC6160318 | biostudies-literature

Differential effects of ontamalimab versus vedolizumab on immune cell trafficking in intestinal inflammation and IBD

Project description:The anti-MAdCAM-1 antibody ontamalimab demonstrated efficacy in a phase II trial in UC and results of early terminated phase III trials are pending, but its precise mechanisms of action are still unclear. Thus, we explored the mechanisms of ontamalimab and compared it to the anti-α4β7 antibody vedolizumab.

2023-06-05 | GSE230059 | GEO

Response of expanded human conventional and regulatory T cells to CD28 or TNFR2 costimulation [Exp2]

Project description:Immune responses depend on a dynamic balance between the opposing activities of conventional (Tconv) and regulatory (Treg) CD4+ T cells. While receptor-targeted approaches have been developed based on their modulation of Tconv cells, Tconv and Treg cells share many costimulatory receptors. We aim to determine key differential signaling events downstream of costimulation to find opportunities for selective manipulation of Tconv or Treg cells. This data set includes the transcriptomes of expanded human Tconv and Treg cells that were treated with anti-CD3, anti-CD3/CD28 or anti-CD3/TNFR2 agonistic mAbs for 24 hours.

2020-07-10 | GSE138604 | GEO

Strength of CD28 costimulation directs self-renewal or differentiation of TCF-1+ PD-1+ CD8 T cells through metabolic regulation

Project description:During persistent antigen stimulation, such as in chronic infections and cancer, T cells differentiate into a hypofunctional exhausted state to survive. Exhausted PD-1+ CD8 T cell responses are sustained by TCF-1+ precursors (Tpex) that self-renew or differentiate into exhausted T cells (Tex) that retain some effector function. Tpex have high expression of the costimulatory molecule CD28 and are the cells that respond to PD-1 targeted immunotherapy. Here, we demonstrate that abrogation of CD28 signaling impairs maintenance of anti-viral T cell responses during chronic infection. Low-level CD28 signaling was required to preserve mitochondrial fitness and self-renewal of Tpex, whereas stronger CD28 signaling enhanced glycolysis and promoted Tpex differentiation. Our findings show that CD28 signaling is essential for long-term maintenance of antigen-specific T cells during chronic stimulation, and suggest that the activation status of antigen presenting cells determines Tpex differentiation into more functional effector-like Tex cells.

2023-07-01 | GSE200506 | GEO

Vedolizumab efficacy is associated with decreased intracolonic dendritic cells, not memory T cells [P444]

Project description:Background: Vedolizumab, an antibody blocking integrin α4β7, is a safe and effective therapy for Crohn’s disease and ulcerative colitis. Blocking α4β7 from binding its cognate addressin MAdCAM-1 on intestinal blood vessel endothelial cells prevents T cells from migrating to the gut mucosa in animal models. However, data supporting this mechanism of action in humans is limited. Methods: We conducted a cross-sectional case-control study to evaluate the effect of vedolizumab on intestinal immune cell populations while avoiding the confounding effect resolving inflammation could have on the cellularity of the colonic mucosa in treatment-responsive patients. Colon biopsies from 71 case patients receiving vedolizumab were matched with biopsies from 71 control patients, similar in disease type, medications, anatomic location, and inflammation. Biopsies were analyzed by flow cytometry and full mRNA transcriptome sequencing of sorted T cells. Results: No difference was seen between vedolizumab recipients and controls in the quantity of any antigen-experienced lymphocyte subset, nor the quality of the transcriptome in any experienced T cell subset. Fewer naïve colonic B and T cells were seen in vedolizumab recipients than controls, regardless of response. The only immune population that was significantly reduced exclusively in the colonic mucosa of vedolizumab-responsive patients was CD1c+ (BDCA1+) dendritic cells. In blood, these dendritic cells ubiquitously express more α4β7 per cell than almost any other circulating leukocyte, but rapidly downregulate α4β7 expression upon vedolizumab exposure. Conclusions: The clinical efficacy of vedolizumab thus reveals integrin α4β7-dependent dendritic cell migration to the intestinal mucosa to be central to IBD pathogenesis.

2023-08-01 | GSE234981 | GEO

Vedolizumab efficacy is associated with decreased intracolonic dendritic cells, not memory T cells [P430]

2023-08-01 | GSE234736 | GEO

CD28 costimulation regulates genome-wide effects on alternative splicing.

Project description:CD28 is the major costimulatory receptor required for activation of naïve T cells, yet CD28 costimulation affects the expression level of surprisingly few genes over those altered by TCR stimulation alone. Alternate splicing of genes adds diversity to the proteome and contributes to tissue-specific regulation of genes. Here we demonstrate that CD28 costimulation leads to major changes in alternative splicing during activation of naïve T cells, beyond the effects of TCR alone. CD28 costimulation affected many more genes through modulation of alternate splicing than by modulation of transcription. Different families of biological processes are over-represented among genes alternatively spliced in response to CD28 costimulation compared to those genes whose transcription is altered, suggesting that alternative splicing regulates distinct biological effects. Moreover, genes dependent upon hnRNPLL, a global regulator of splicing in activated T cells, were enriched in T cells activated through TCR plus CD28 as compared to TCR alone. We show that hnRNPLL expression is dependent on CD28 signaling, providing a mechanism by which CD28 can regulate splicing in T cells and insight into how hnRNPLL can influence signal-induced alternative splicing in T cells. The effects of CD28 on alternative splicing provide a newly appreciated means by which CD28 can regulate T cell responses.

| S-EPMC3386953 | biostudies-literature

Sialic Acid Ligands of CD28 Suppress Costimulation of T Cells.

Project description:Effector T cells comprise the cellular arm of the adaptive immune system and are essential for mounting immune responses against pathogens and cancer. To reach effector status, costimulation through CD28 is required. Here, we report that sialic acid-containing glycans on the surface of both T cells and APCs are alternative ligands of CD28 that compete with binding to its well-documented activatory ligand CD80 on the APC, resulting in attenuated costimulation. Removal of sialic acids enhances antigen-mediated activation of naïve T cells and also increases the revival of effector T cells made hypofunctional or exhausted via chronic viral infection. This occurs through a mechanism that is synergistic with antibody blockade of the inhibitory PD-1 axis. These results reveal a previously unrecognized role of sialic acid ligands in attenuation of CD28-mediated costimulation of T cells.

| S-EPMC8461770 | biostudies-literature

A multi-omics approach to understand and predict therapeutic success of anti-TNF and anti-integrin agents in inflammatory bowel disease

Project description:In this study we wanted to identify baseline predictors of successful anti-TNF and vedolizumab therapy in patients with inflammatory bowel disease (based on tissue transcriptomics and CD4/CD14 transcriptomics)

2023-10-31 | E-MTAB-7914 | biostudies-arrayexpress

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