Cluster of Differentiation 28 (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) (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 cellular 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.

Recent Publications Summary

Recent studies have continued to examine CD28 as a central costimulatory target in T cell biology and immunotherapy. In CAR T-cell systems, endogenous CD28 signaling was shown to support persistent antitumor activity in multiple myeloma and lymphoma models, where blockade of CD28 interaction with CD80/86 accelerated tumor regrowth, while CD28 knockout in 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 41627211Feb. A related commentary emphasized that endogenous CD28 cooperates with 4-1BB signaling to enhance CAR T-cell metabolic fitness, proliferation, sustained function, and therapeutic efficacy 41848361Mar.

Mechanistic work also linked CD28 to early fate decisions in CAR T cells through asymmetric cell division. In this study, CD28-containing 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, correlating with reduced long-term persistence 42332264Jun. By contrast, 4-1BB CAR T cells exhibited less surface polarization but more pronounced molecular divergence, yielding proximal effector-prone and distal persistence-prone daughters 42332264Jun. Together, these findings suggest that CD28 costimulation shapes memory fate acquisition and persistence through early asymmetric division programs 42332264Jun.

CD28 has also been investigated as a cancer-cell target rather than solely a T-cell costimulatory receptor. A tumor-specific lipid nanoparticle platform was developed to deliver Cd28 siRNA selectively to malignant cells while avoiding T-cell sequestration, exploiting altered tumor lipid metabolism and lysophosphatidylcholine acyltransferase uptake mechanisms 42261788Jun. In vivo, this approach knocked down cancer cell CD28, reduced PD-L1 expression, and overcame anti-PD-1 resistance, with associated remodeling of the immunosuppressive tumor microenvironment, including increased CD8+ T cell infiltration and dendritic cell involvement 42261788Jun.

Clinical and translational studies have also targeted CD28 directly with an anti-CD28 PEGylated monoclonal antibody fragment. VEL-101 (pegrizeprument) was evaluated in a randomized, double-blind, placebo-controlled, dose-escalation phase 1 study in healthy participants to assess safety, pharmacokinetics, and pharmacodynamics of fixed-dose subcutaneous and intravenous administration 42083151May. In addition, CD28 appeared in an 8-gene melanoma signature associated with prognosis, immune features, and drug sensitivity, alongside CD80, CD86, CTLA4, FAS, IFNG, and IL10, underscoring its relevance to immune microenvironment analyses in cancer 42216340May. CD28 was also included among immune markers tested for cross-reactivity of commercial monoclonal antibodies in buffaloes, reflecting its use as an immunological cell-surface marker in comparative immunology studies 41864098Mar.

What Changes, What Holds

1. Endogenous CD28 remains a functional support for CAR T-cell persistence, but its effects are context-dependent
REINFORCES Work in engineered T cells sharpens the baseline view that CD28 is a major costimulatory driver of proliferation, survival, and metabolic fitness. The new data do not replace that role; they show that endogenous CD28 can materially sustain antitumor activity and that removing it can prolong activity in some 4-1BB-costimulated constructs 41627211Feb41848361Mar. The unresolved point is not whether CD28 matters, but how its contribution varies by CAR design and metabolic state.

2. CD28-linked asymmetric division may help explain divergent CAR T-cell fate, but the mechanism is still unsettled
NEW DIRECTION This work adds a developmental layer to the baseline account by tying CD28 costimulation to early daughter-cell fate decisions, a role the Overview does not cover. It suggests that CD28-containing CARs may bias surface polarization and limit durable molecular divergence after the first division, which could help explain weaker persistence 42332264Jun. That is a hypothesis about memory acquisition rather than a contradiction of canonical signaling, and it needs broader validation across constructs and settings.

3. tumor-cell CD28 is becoming a therapeutic liability rather than only a lymphocyte marker
NEW DIRECTION The new work extends the Overview’s note that tumor-intrinsic CD28 can aid immune escape by showing a practical way to exploit that role therapeutically 42261788Jun. It does not overturn the established T-cell costimulatory function; instead, it strengthens the idea that CD28 can be pathogenic when expressed by cancer cells and that selective silencing may reverse PD-1 resistance. The key unsettled issue is specificity: whether tumor-selective delivery can avoid disrupting normal T-cell CD28 biology.

4. Direct CD28 targeting is moving into early clinical testing and broader biomarker use
REINFORCES A first-in-human safety study of an anti-CD28 PEGylated antibody fragment supports the baseline claim that CD28 is therapeutically significant, especially in immunomodulation 42083151May. The melanoma signature and buffalo antibody-cross-reactivity findings do not change CD28 biology; they mainly show that CD28 continues to function as a useful immune marker in translational and comparative studies 42216340May41864098Mar. Together, these are extensions of established utility rather than new biology.

Overview update candidates: asymmetric division as a CD28-linked mechanism in CAR T-cell fate; tumor-selective CD28 silencing as a strategy to overcome PD-1 resistance; early clinical evaluation of direct CD28 blockade.