CD72 is a protein found on the surface of immune cells, primarily B cells, where it exists as two identical halves. It belongs to a family of proteins known as C-type lectins. This protein plays a role in the intricate regulation of the body’s immune responses. CD72 is considered a non-redundant regulator of B-cell development and a negative regulator of B-cell responsiveness.
CD72’s Role in Immune System Regulation
CD72 operates as a co-receptor on B cells. It contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic region, which, upon phosphorylation, recruits and activates the tyrosine phosphatase SHP-1. This recruitment of SHP-1 down-regulates signaling through the B cell receptor (BCR) by dephosphorylating proximal signaling molecules like Syk. This mechanism suggests a negative regulatory role for CD72, preventing excessive B cell activation.
However, CD72 acts as both an inhibitor and, in some contexts, an enhancer of B cell responses. While it can suppress B cell proliferation in response to BCR stimulation, other studies indicate that B cells lacking CD72 can show increased proliferation. CD72 is also involved in maintaining immune tolerance, which is the body’s ability to distinguish between its own healthy cells and foreign invaders, thereby preventing the immune system from attacking itself.
CD72’s regulatory function is partly determined by its binding partners. CD100 (also known as Semaphorin-4D) has been identified as an inhibitory ligand for CD72, though its precise significance is still being clarified. CD72 specifically recognizes certain self-antigens, such as the RNA-containing Sm/RNP, which is a key target in systemic lupus erythematosus. By binding to such self-antigens, CD72 can inhibit B cell responses, contributing to self-tolerance.
CD72 and Autoimmune Disorders
Dysfunction of CD72 is linked to the development of autoimmune diseases, where the immune system mistakenly attacks the body’s own tissues. When CD72’s regulatory role is impaired, B cells can become overactive, leading to the production of harmful autoantibodies. This overactivity contributes to conditions like Systemic Lupus Erythematosus (SLE), characterized by autoantibody production against nuclear antigens and inflammation.
Genetic variations in CD72 are associated with susceptibility to SLE in both humans and mice. For example, a lupus-susceptible allele called CD72c binds less strongly to the self-antigen Sm/RNP compared to the lupus-resistant CD72a allele. This reduced binding affinity contributes to a weaker inhibition of B cell responses to Sm/RNP, leading to anti-Sm/RNP antibodies characteristic of lupus. Mice lacking CD72 (CD72-/- mice) also tend to develop a more severe lupus-like disease, underscoring its role in preventing autoimmunity.
Studies have shown that CD72 expression on B cells is decreased in patients with SLE compared to healthy individuals. This lower expression correlates with increased disease activity, anti-double-stranded DNA (dsDNA) antibodies, and kidney involvement (lupus nephritis). Furthermore, increased levels of soluble CD72 in the serum of SLE patients are associated with higher disease activity and renal involvement.
Targeting CD72 for Therapies
Given its involvement in immune regulation and autoimmune diseases, CD72 is being explored as a potential target for therapeutic interventions. Researchers are investigating ways to modulate CD72 activity to treat autoimmune diseases and certain cancers. This involves either enhancing its inhibitory function in autoimmune disorders or, conversely, blocking its activity in certain cancers where B cell suppression might be undesirable.
One approach involves using antibodies or small molecules to influence CD72 function. In B-cell malignancies, where low surface antigen density can reduce the effectiveness of existing therapies, CD72 is a promising target. Chimeric antigen receptor (CAR) T-cell therapies targeting CD72 are being developed, particularly for B-cell cancers resistant to CD19-directed therapies. These CD72-targeting nanobody-based CAR T-cells (nanoCARs) have shown promise in preclinical models for eliminating B-cell acute lymphoblastic leukemia and B-cell non-Hodgkin’s lymphoma.
Researchers are also exploring ways to increase CD72 surface antigen density on tumor cells, for instance, by using small molecules like bryostatin, to enhance the efficacy of CD72-targeting therapies. The development of humanized anti-CD72 nanobodies aims to improve the potency of these nanoCARs, making them more effective therapeutic candidates. These strategies represent a focused effort to leverage CD72’s regulatory properties for the development of new treatments in conditions where immune cell activity is dysregulated.