CD28
CD28
Overview
CD28 (Cluster of Differentiation 28) is a co-stimulatory receptor expressed predominantly on the surface of T lymphocytes, encoded by the CD28 gene in humans. It plays a central and non-redundant role in adaptive immune activation: upon ligation with its natural ligands CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells such as dendritic cells, CD28 delivers a critical secondary signal that, together with T-cell receptor (TCR) engagement, drives T-cell proliferation, survival, cytokine production, and metabolic reprogramming. Without this costimulatory signal, T cells may become anergic or undergo apoptosis rather than mounting an effective immune response. CD28 signaling activates downstream pathways including PI3K/AKT and NF-κB, promoting glucose uptake, mitochondrial fitness, and the transcription of pro-survival genes. Its counterpart receptor, cytotoxic T-lymphocyte associated protein 4 (CTLA-4), competes for the same ligands with higher affinity and delivers inhibitory signals, establishing a fundamental checkpoint axis that regulates immune tolerance and self-reactivity.
Beyond its canonical role in T-cell biology, CD28 has emerged as a therapeutically significant molecule in transplantation immunology, immuno-oncology, and CAR T-cell engineering. Loss or downregulation of CD28 on CD8+ T cells is a well-characterized marker of T-cell aging and exhaustion, with implications for immune senescence and diminished responses to infection and cancer. Conversely, tumor-intrinsic expression of CD28 has recently been recognized as a non-classical mechanism of immune escape, expanding the biological relevance of this receptor well beyond lymphocytes. These dual roles—essential costimulator in beneficial immunity and potential driver of immune evasion when co-opted by cancer cells—make CD28 one of the most multifaceted targets in contemporary biomedical research.
Focus of Latest Publications
Recent publications have focused on CD28 in several distinct biomedical contexts, especially cancer immunotherapy and immune regulation. In CAR T-cell studies, CD28 has been examined both as an engineered costimulatory domain and as an endogenous signaling molecule. One study comparing CD28 and 4-1BB costimulatory domains found that CD28 CAR T cells showed higher CAR surface expression and greater surface proteome asymmetry after the first division, but paradoxically displayed less transcriptional, epigenetic, and metabolic divergence between daughter cells, which correlated with reduced long-term persistence. In contrast, 4-1BB CAR T cells exhibited more pronounced divergence between proximal effector-prone and distal persistence-prone daughters, highlighting how costimulatory signaling can shape asymmetric cell division and early fate decisions.
Additional CAR T-cell work showed that endogenous CD28 signaling contributes to therapeutic activity rather than simply acting as a redundant pathway. In preclinical multiple myeloma and lymphoma models, blockade of CD28 interaction with CD80/86 unexpectedly accelerated tumor regrowth, while knockout studies demonstrated that endogenous CD28 on 4-1BB costimulated CAR T cells prolonged in vivo activity, reprogrammed mitochondrial metabolism to maintain redox balance, and promoted proliferation and inflammatory cytokine release in the tumor microenvironment. A related commentary emphasized that endogenous CD28 signaling cooperates with 4-1BB to support CAR T-cell metabolic fitness, persistence, and antitumor function.
CD28 has also been explored as a cancer target outside the CAR T-cell setting. A tumor-specific lipid nanoparticle platform was developed to deliver CD28 siRNA selectively to tumor cells, based on the observation that cancer cell-intrinsic CD28 can function as a non-classical RNA-binding protein that stabilizes CD274 mRNA and supports immune escape. In murine breast and lung cancer models, this approach knocked down most tumor-cell CD28, reduced PD-L1 expression, increased CD8+ T-cell infiltration and dendritic cell activation, extended survival, and overcame resistance to anti-PD-1 therapy. These findings support selective inhibition of tumor-intrinsic CD28 as a strategy to remodel the tumor microenvironment while avoiding interference with T-cell costimulation.
Beyond oncology, CD28 has appeared in translational immunology and biomarker studies. A phase 1 study evaluated VEL-101, a monovalent anti-CD28 PEGylated monoclonal antibody fragment, as a fixed-dose subcutaneous or intravenous maintenance immunosuppressant under development for kidney transplant recipients, with the trial designed to assess safety, pharmacokinetics, and pharmacodynamics in healthy participants. CD28 was also included in an 8-gene melanoma prognostic signature linked to survival and immune infiltration, and in a buffalo immunophenotyping study where a commercial anti-CD28 monoclonal antibody was validated for cross-reactivity in flow cytometry. In a Mendelian randomization analysis of gut microbiota, cerebrospinal fluid proteins, and aging-related outcomes, CSF protein CD28 was identified as a mediator of the causal effect of Streptococcus on longevity, suggesting a possible role in gut-brain axis biology.