CD28 Negative T Cells: Is Their Loss Our Gain?

Abstract

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 post-transplant immune management.

CTLA4-Ig in combination with FTY720 promotes allograft survival in sensitized recipients

“…We acknowledge an important caveat of this mouse model, namely that CD28-negative terminally differentiated T cells that are present in significant frequencies in humans are absent in our immunized mice. CD28-negative cells have been found mostly within the CD8 + subset, and comprises T cells with suppressive, exhausted, or effector activity (29). Therefore, depending on the properties of CD28-negative cells present in the transplant recipient, it is possible that the efficacy of CTLA4-Ig observed in our mouse model may be an overestimate of its effects in humans.…”

CD28 Costimulation: From Mechanism to Therapy

“…These cells represent a population of antigen-experienced cells that may have either pro- or anti-inflammatory characteristics (Boucher et al, 1998; Strioga et al, 2011). In solid organ transplant recipients, CD8+CD28− cells have been found to undergo oligoclonal expansion and may play a suppressive role and promote allograft tolerance (Manavalan et al, 2004; Mou et al, 2014). Indeed, in kidney transplant recipients CD8+CD28− T cells may be protective against organ rejection (Trzonkowski et al, 2008), implying a possible immunosuppressive role for this subset.…”

“…Indeed, CD28 negative cells are heterogeneous and many have pro- or anti-inflammatory effects in different contexts (Mou et al, 2014), making simple quantitation from peripheral blood samples difficult to interpret. Restoring CD28 expression in human T cells slows replicative senescence through increased telomerase activity, increased proliferative potential, and decreased secretion of inflammatory cytokines (Parish et al, 2010).…”

Viral-induced CD28 loss evokes costimulation independent alloimmunity

“…High proportions of CD28 - T cells have been observed in human diseases, including inflammatory syndromes, chronic infections, and cancer. 1 Human CD28 - T cells are functionally active, resistant to apoptosis, and limited in proliferative capacity. Though well known in humans, CD28 loss has not been well characterized in mice.…”