Use of CD28 agonists to refill the T-cell tank?

T-cell lymphopenia with a restricted T-cell diversity creates a long-lasting state of immuno-suppression following autologous and, particularly, allogeneic hematopoietic stem cell transplantation. In addition, delayed T-cell reconstitution following control of viral replication in HIV-infected adults leads to continued susceptibility to opportunistic infections and is a barrier to immunization. In this issue, Elflein and colleagues (page 1764) report the induction of CD28-driven T-cell expansion in lymphopenic rats in vivo following anti-CD28 monoclonal antibody therapy. Two injections of an agonistic CD28 antibody were shown to dramatically accelerate repopulation of T cells, and the resulting T cells had a broad repertoire and were functional, suggesting that treatment with human CD28–specific agonists could protect T-lymphopenic patients from opportunistic infections.

CD28 ligation by natural ligands CD80 and CD86 is required for the induction of antigen-driven T-cell proliferation of naive T cells. Antibodies to CD28 may not always mimic the function of natural ligands— Nunès and colleagues previously showed that a panel of CD28 antibodies had distinct effects on T-cell signal transduction (Nunès et al, Int Immunol. 1993;5:311-315). CD28 antibodies that are mitogenic in vitro in the absence of antigen signals have been raised in several laboratories, and Elflein et al have shown that it is likely that the properties of mitogenic CD28 antibodies are governed by the epitope of CD28 recognized by the antibody, as well as the avidity.

In neonates, peripheral T cells are derived from thymic emigrants. In adults, early T-cell reconstitution following cytotoxic therapy is primarily the result of proliferation of peripheral T cells, a process referred to as homeostatic proliferation. The processes that regulate homeostatic T-cell proliferation are complex, but it is clear that the cytokines interleukin 7 (IL-7) and IL-15 have an essential role in this process. In addition, mice engineered to have increased or decreased CD80 or CD86 expression indicate that B7 costimulation plays a physiologic role in the regulation of CD4⁺ and CD8⁺ T-cell homeostasis (see Yu et al, J Immunol. 2000;164:3543-3553). Thus, the study by Elflein et al suggests that CD28 agonists could have therapeutic potential for lymphopenia.