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.

Key Publications

• NEWJun Fate induction through asymmetric T cell division is modulated by chimeric antigen receptor costimulatory domains. (Nature immunology, 2026, PMID 42332264): "All US Food and Drug Administration-approved CAR T cell products incorporate either 4-1BB or CD28 costimulatory domains, each conferring distinct phenotypic outcomes, but how these signals control early fate decisions is incompletely understood."
• NEWJun Tumor-Specific Delivery of CD28 siRNA via Lyso-PC C-16 Modified Lipid Nanoparticles Overcomes Anti-PD-1 Resistance by Remodeling Tumor Microenvironment. (Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026, PMID 42261788): "While cancer cell-intrinsic CD28 facilitates immune escape by functioning as a non-classical RNA-binding protein to stabilize CD274 (PD-L1) mRNA, inhibiting this pathway in cancer cells without impairing essential T cell CD28 costimulation remains a major structural challenge."
• May Vasoactive intestinal peptide associated 8-gene signature with prognostic and immune associations in melanoma. (Medicine, 2026, PMID 42216340): "In melanoma, we identified an 8-gene signature (CD28, CD80, CD86, CTLA4, FAS, IFNG, IL10, and IL12A) associated with survival."
• Jun Safety, Pharmacokinetics, and Pharmacodynamics of Fixed-dose, Subcutaneous, and Intravenous Administration of VEL-101, an Anti-CD28 PEGylated Monoclonal Antibody Fragment, in Healthy Participants: A Randomized, Double-blind, Placebo-controlled, Dose Escalation, Phase 1 Study. (Transplantation, 2026, PMID 42083151): "VEL-101, also known as pegrizeprument, is a monovalent, humanized, anti-CD28 PEGylated monoclonal antibody fragment that selectively blocks CD28 costimulation, under development as a maintenance immunosuppressant in kidney transplant recipients."
• May Evaluation of cross-reactivity of monoclonal antibodies against cytokines and cellular molecules of bovine and human origin to identify immunological markers in buffaloes (Bubalus bubalis). (Veterinary immunology and immunopathology, 2026, PMID 41864098): "sixteen commercial mAbs anti-cell markers (CD4, CD8, CD14, CD21, CD25, CD28, CD45RB, CD45RO, WC1, and CD80) and anti-cytokines or other effector molecules of the immune system (TNF-α, IFN-γ, IL-4, IL-17A, granzyme B and perforin) that recognize molecules from bovine and human species were evaluated in whole blood samples from buffaloes and cattle."
• May Two Costimulations Are Better Than One: Role of Endogenous CD28 in 4-1BB CAR T Cells. (Blood cancer discovery, 2026, PMID 41848361): "Liberman and colleagues identify endogenous CD28 signaling as a regulator of 4-1BB chimeric antigen receptor (CAR) T-cell function by promoting metabolic fitness, proliferation, and sustained antitumor function."
• May Endogenous CD28 Drives the Persistent Activity of CAR T Cells in Myeloma and Lymphoma Models. (Blood cancer discovery, 2026, PMID 41627211): "Consequently, we sought to determine if inhibition of CD28 survival signaling could increase multiple myeloma sensitivity to CAR T-cell therapy."
• Apr Identification of gut microbiota causally associated with aging and longevity and mediation roles of the cerebrospinal fluid proteins: proteomic genetic evidence from Mendelian randomization. (GeroScience, 2026, PMID 40702285): "Mediation MR analysis found that CSF protein CD28 mediated the causal effects of Streptococcus on longevity (mediation proportion 11.7%, P=0.0394)."