CD28 negative T cells: Is their loss our gain?

CD28 is a primary costimulation molecule for T cell activation. However, during the course of activation some T cells lose this molecule and assume a CD28-independent existence. These CD28^- T cells are generally antigen-experienced and highly differentiated. CD28^- T cells are functionally heterogeneous. Their characteristics vary largely on the context in which they are found and range from having enhanced cytotoxic abilities to promoting immune regulation. Thus, CD28 loss appears to be more of a marker for advanced differentiation regardless of the cytotoxic or regulatory function being conducted by the T cell. CD28^- T cells are now being recognized as playing significant roles in several human diseases. Various functional CD28^- populations have been characterized in inflammatory conditions, infections and cancers. Of note, the recent introduction of costimulation blockade-based therapies, particularly those that inhibit CD28-B7 interactions, has made CD28 loss particularly relevant for solid organ transplantation. Certain CD28^- T cell populations seem to promote allograft tolerance whereas others contribute to alloreactivity and costimulation blockade resistant rejection. Elucidating the interplay between these populations and characterizing the determinants of their ultimate function may have relevance for clinical risk stratification and personal determination of optimal posttransplant immune management. The authors provide an overview of the circumstances leading to loss of the critical T cell costimulatory molecule CD28, and they discuss the transplant-relevant consequences of this sign of progressive T cell maturation.