Memory T cells need CD28 costimulation to remember

Abstract

The activation and expansion of naïve T cells require costimulatory signals provided by CD28 and TNF family members. In contrast, for many years it was believed that memory T cells do not require CD28 costimulation for expansion during secondary responses. This was based on in vitro experiments that suggested the re-activation of memory T cells is somewhat independent of costimulation. Recent in vivo evidence, however, has challenged this and shown that both CD4+ and CD8+ memory T cells require CD28 costimulation for maximal expansion and pathogen clearance. This requirement has important implications for host immunity, vaccine development and immunotherapeutics.

Fig. 1

The effect of CD28 costimulation on the quality and expansion of memory T cells. Activation of naïve T cells by APCs such as DC expressing MHC/peptide complexes and CD28 ligands, leads to intense proliferation and clonal expansion. Memory T cells generated after a primary response expand rapidly upon re-encountering antigen and CD28 costimulation. When memory cells re-encounter antigen without sufficient CD28 costimulation, they fail to fully expand and clear pathogens. If naïve T cells are activated by APCs in the absence of CD28 costimulation, there is limited clonal expansion or even anergy. The resulting memory population is normal in terms of quantity but quality is affected and these memory cells do not re-expand optimally upon antigen re-encounter.

Fig. 2

Pathogens, tumors and immunotherapeutics can impair memory T cell activation. In contrast to a healthy immune response in which memory T cells receive both signal 1 and signal 2 (costimulation), the immune response against some viruses or tumors or during ageing may be impaired due to downregulation of costimulatory ligands. Blocking costimulation, although beneficial in autoimmunity and transplantation for diminishing the activation of auto- and alloantigen specific responses, may impair the memory T cell responses induced by previous vaccinations infections.