CD8 T cells: too selfish to share IL-2

CD8 T cells play a pivotal role in body's defense against viral infections. While it is relatively easy to see activation of CD8 T cells against a real infectious virus, nominal, non-replicative antigens (used in many vaccines) have a hard time to mimic it. In general, CD4 T cell help and antigen presentation by dendritic cell (DC) are required to activate CD8 T cell. In 1998, three articles published back to back in Nature showed that one mechanism of CD4 T cell help was through CD40L-triggered DC (called licensing). Later, another mechanism has been discovered: help through IL-2 signaling in CD8 T cells. Both mechanisms, however, created some confusion in scientific community. The point is that both CD40L as well as IL-2 can be expressed by all three types of cell involved in CD8 T cell activation: CD4 helper cell, DC and CD8 T cell. The debate then and now is about what kind of cell (CD4, DC, CD8) has to express CD40L or IL-2 to provide biologically significant help for CD8 T cell activation.

If you are interested to know more about “help” signal to CD8 T cell, I will recommend to read the new article from Steve Schoenberger's Lab (one of the author of the original 1998 paper) published recently in Nature Immunology. In the study by Sonia Feau et al (1), the author showed that CD8 T cell activation or it's memory formation was comparable whether CD4 T cells could express IL-2 or not. CD40L blockade, however, inhibited CD8 T cell response. No data are provided, however, to understand whether CD40L expression on CD4 T cell (or other cell types) was involved here. The critical data are in Fig. 3 and 4. In Figure 3, using infectious virus, the author showed that IL-2-deficient CD8 T cells expanded less compare to IL-2-sufficient CD8 T cells. Interestingly, IL-2-deficient CD8 T cells behaved exactly as if IL-2-sufficient CD8 T cells (in mouse)-depleted of CD4 T cells. Another critical point is that in CD4 T cell-depleted host, the expansion of endogenous, wild-type CD8 T cells was more reduced in the presence of IL-2-deficient donor CD8 T cells compared to IL-2-sufficient donor CD8s (Fig. 3c). This is in contrast to Fig. 4C, where the reduction is equivalent (here the antigen is non-infectious in nature).

CD8 T cells do produce IL-2 but its biological role was dismissed or ignored until now. After reading this articles, one question comes to my mind is if CD8 T cell can produce IL-2 and can express CD40L, why there is a need for CD4 T cell help?

David Usharauli