Fig. 11.32 CD4 T cells are required for the development of functional CD8 memory T cells. Mice that do not express MHC class II molecules (MHC II–/–) fail to develop CD4 T cells. Wild-type and MHC II–/– mice were infected with Listeria monocytogenes expressing the model antigen ovalbumin (LM-OVA). After 7 days, the number of OVA-specific CD8 T cells can be measured by using specific MHC tetramers that contain an OVA peptide, and therefore bind to T-cell receptors that react with this antigen. After 7 days of infection, mice lacking CD4 T cells were found to have the same number of OVA-specific CD8 T cells as wild-type mice. However, when mice were allowed to recover for 60 days—a time during which memory T cells could develop—and were then re-challenged with LM-OVA, the mice lacking CD4 T cells failed to expand CD8 memory cells specific to OVA, whereas there was a strong CD8 memory response in the wild-type mice.
This requirement for CD4 help in CD8 memory generation has also been demonstrated by experiments in which CD4 T cells were depleted by treatment with antibody or in which mice were deficient in the CD4 gene.
The mechanism underlying this requirement for CD4 T cells is not completely understood. It may involve two types of signals received by the CD8 T cell— those received through CD40 and those received through the IL-2 receptor. CD8 T cells that do not express CD40 are unable to generate memory T cells. Although many cells could potentially express the CD40 ligand needed to stimulate CD40, it is most likely that CD4 T cells are the source of this signal.
The requirement for IL-2 signaling in programming CD8 memory was discovered by using CD8 T cells that were unable to respond to IL-2 because of a genetic deficiency in the IL-2Rα subunit. Because IL-2Rα signaling is required for the development of T cells, mice lacking IL-2Rα develop a lymphopro liferative disorder. However, this disorder does not develop in mice that are mixed bone marrow chimeras harboring both wild-type and IL-2Rα-deficient cells, and these chimeras can be used to study the behavior of IL-2Rα-deficient cells. When these chimeric mice were infected with LCMV and their responses were tested, memory CD8 responses were found to be defective specifically in the T cells lacking IL-2Rα.
The experiment shown in Fig. 11.33 indicates that, distinct from their effect in programming naive CD8 T cells, CD4 T cells also provide help in maintaining the number of CD8 memory T cells. In this case, CD8 memory T cells that had been programmed in normal mice were transferred into immunologically naive mice that either expressed or lacked MHC class II. Transfer of CD8 memory cells into mice lacking MHC class II resulted in a more rapid decrease in the number of memory CD8 T cells in comparison with a similar transfer
Fig. 11.33 CD4 T cells promote the maintenance of CD8 memory cells. The dependence of memory CD8 T cells on CD4 T cells is shown by the different lifetimes of the memory cells after their transfer into host mice that either have normal CD4 T cells (wildtype) or lack CD4 T cells (MHC II–/–). In the absence of MHC class II proteins, CD4 T cells fail to develop in the thymus. When CD8 memory T cells specific for LCMV were isolated from donor mice 35 days after infection with the virus and transferred into these hosts, memory cells were maintained only in mice that had CD4 T cells. The basis for this action of CD4 T cells is not yet clear, but has implications for conditions such as HIV/AIDS in which the number of CD4 T cells is diminished.