Immunotherapy to CD5, a T-cell antigen having roles from development to peripheral function: Future prospective and challenges.

CD5 is a pan T-cell marker expressed by all T-cells and a subset of B-cells, i.e., B1a cells. The significance of CD5 is evident from its functions, starting from T-cell development, antigen priming, activation, and effector response to the maintenance of tolerance. Varying CD5 expression and signaling in response to TCR-pMHC complex avidity is associated with thymic selection, competency, and effector response. Altered CD5 expression is associated with immunological and diseased conditions such as CD5^-/low infiltrating T-cells in solid tumors, CD5^hi T-cells in anergy conditions, CD5^-/low phenotype of leukemic T-cells, high CD5 expression by regulatory T-cells, CD5^lowphenotype of autoreactive T-cells, etc. A low CD5 expression triggers activation-induced cell death upon antigenic stimulation. There are three forms of CD5: membrane CD5 (mCD5), intracellular CD5 (cCD5) and soluble CD5 (sCD5). mCD5 and cCD5 are generated from conventional and non-conventional mRNA variants, i.e., E1A and E1B, respectively. E1B variant encoding cCD5 is derived from a human endogenous retrovirus segment inserted 8.2 kb upstream to conventional E1A exon. Various conditions, such as leukemia, exposure to hydrocarbon, hypoxia, etc., can trigger E1B transcription and, thus, cCD5 expression. Blocking mCD5 with mAb can restore immune response, effectively targeting cancer. Understanding cCD5, linked to leukemogenesis, can offer new avenues of immunotherapy.