Cluster of Differentiation 28 (CD28)

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 Phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (PKB) 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.