ArticleProceedings of the National Academy of Sciences of the United States of America2015
CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 113 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
113 citing papers in PubMed, 1 synthesis or guideline pooled it, 169 citations in OpenAlex.
- A meta-analysis of the association between CTLA-4 genetic polymorphism and susceptibility of asthma.Medicine · 2018Pooled it
- Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes.Nature immunology · 2020Trial
- Abatacept Targets T Follicular Helper and Regulatory T Cells, Disrupting Molecular Pathways That Regulate Their Proliferation and Maintenance.Journal of immunology (Baltimore, Md. : 1950) · 2019Trial
- Non-parametric Heat Map Representation of Flow Cytometry Data: Identifying Cellular Changes Associated With Genetic Immunodeficiency Disorders.Frontiers in immunology · 2019Trial
- Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation.The Journal of allergy and clinical immunology · 2018Trial
- Long-Term Outcomes in Belatacept- Versus Cyclosporine-Treated Recipients of Extended Criteria Donor Kidneys: Final Results From BENEFIT-EXT, a Phase III Randomized Study.American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons · 2016Trial
- Regulation of follicular helper T cell subset differentiation in health and disease.Journal of molecular medicine (Berlin, Germany) · 2026Review
- Autosomal recessive human CTLA-4 deficiency with autoimmune infiltration.Journal of human immunity · 2026Article
- CAR19 Tregs treat murine chronic graft-versus-host disease through immune suppression without measurable B cell cytolysis.JCI insight · 2026Article
- Immune Checkpoint Inhibitor-Associated Inflammatory Arthritis.Arthritis & rheumatology (Hoboken, N.J.) · 2026Review
- Anti-PD-1 plus anti-CTLA-4 blockade overcomes immune exclusion in NSCLC brain metastases by enhancing CD8Nature communications · 2026Article
- Low-dose radiotherapy remodels the tumor immune microenvironment via the cGAS-STING pathway: mechanisms, challenges, and combination therapy strategies.Molecular cancer · 2026Review
- TIGITFrontiers in immunology · 2026Review
- Mendelian Randomization and Experimental Validation Identify Key Immune Signatures in Bullous Pemphigoid.Clinical, cosmetic and investigational dermatology · 2026Article
- Next-Generation Immune Checkpoints and Tumor Microenvironment Modulation in Cancer Immunotherapy.Journal of immunology research · 2026Review
- T follicular helper cells in primary immune regulatory disorders.The Journal of allergy and clinical immunology · 2025Review
- The Role of Abatacept on Inflammation and Fibrosis in Hypochlorous Acid-Induced Fibrosis Mice.International journal of rheumatic diseases · 2025Article
- Multifaceted function of B cells in tumorigenesis.Frontiers of medicine · 2025Review
- Signaling Activation and Modulation in Extrafollicular B Cell Responses.Immunological reviews · 2025Review
- Efficacy of CTLA-4 checkpoint therapy is dependent on IL-21 signaling to mediate cytotoxic reprogramming of PD-1Nature immunology · 2025Article
53 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an essential regulator of T-cell responses, and its absence precipitates lethal T-cell hyperactivity. However, whether CTLA-4 acts simply to veto the activation of certain clones or plays a more nuanced role in shaping the quality of T-cell responses is not clear. Here we report that T cells in CTLA-4-deficient mice show spontaneous T-follicular helper (T(FH)) differentiation in vivo, and this is accompanied by the appearance of large germinal centers (GCs). Remarkably, short-term blockade with anti-CTLA-4 antibody in wild-type mice is sufficient to elicit T(FH) generation and GC development. The latter occurs in a CD28-dependent manner, consistent with the known role of CTLA-4 in regulating the CD28 pathway. CTLA-4 can act by down-regulating CD80 and CD86 on antigen presenting cells (APCs), thereby altering the level of CD28 engagement. To mimic reduced CD28 ligation, we used mice heterozygous for CD28, revealing that the magnitude of CD28 engagement is tightly linked to the propensity for T(FH) differentiation. In contrast, other parameters of T-cell activation, including CD62L down-regulation and Ki67 expression, were relatively insensitive to altered CD28 level. Altered T(FH) generation as a result of graded reduction in CD28 was associated with decreased numbers of GC B cells and a reduction in overall GC size. These data support a model in which CTLA-4 control of immunity goes beyond vetoing T-cell priming and encompasses the regulation of T(FH) differentiation by graded control of CD28 engagement.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.