The distinction between TCM, TEM, and TRM memory populations has been made both in humans and in the mouse. However, each subset itself is not strictly a homogeneous population. For example, within the CCR7-expressing TCM cells, there are cells with differing expression of other markers, particularly chemokine receptors. A subset of the CCR7-positive TCM cells also express CXCR5, similarly to TFH cells, although it is not yet clear whether these memory cells can provide help to B cells in the germinal center.
On stimulation by antigen, TCM cells rapidly lose expression of CCR7 and differentiate into TEM cells. TEM cells are also heterogeneous in the chemokine receptors they express, and have been classified according to chemokine receptors typical of TH1 cells (CCR5), TH17 cells (CCR6), and TH2 cells (CCR4). Central memory cells do not appear committed to particular effector lineages,
Fig. 11.31 Tissue-resident memory T cells are a major immune compartment that surveys peripheral tissues for reinfection by pathogens. After activation and priming in lymphoid tissues, activated CD8 and CD4 T cells enter the blood and enter tissues in response to various chemokines, as shown here for entry into the dermis, guided by expression of CXCR3. The reexpression of CD69 by T cells caused by antigen or other unknown signals leads to decreased S1PR1 surface expression, promoting retention of these cells in the dermis. In response to TGF-β, some cells induce integrin αE:β7 (CD103), which binds E-cadherin expressed by epithelial cells, promoting entry and retention of T cells in the epidermis, where many CD8 TRM cells reside. Recent estimates indicate that TRM cells may outnumber the recirculating T cells that migrate through the body.
and even effector memory cells are not fully committed to the TH1, TH17, or TH2 lineage, although there is some correlation between their eventual output of TH1, TH17, or TH2 cells and the chemokine receptors expressed. Further stimulation with antigen seems to drive the differentiation of effector memory cells gradually into the distinct effector T-cell lineages.
11-23 CD4 T-cell help is required for CD8 T-cell memory and involves CD40 and IL-2 signaling.
There is experimental evidence that CD4 T cells play an important role in programming optimal CD8 T-cell memory. In the experiment shown in Fig. 11.32, the primary and memory CD8 T-cell responses were compared between wild-type mice and mice that lack expression of MHC class II, and which therefore have a defect in CD4 T cells. In this experiment, the CD8 T-cell response was measured against a protein, ovalbumin, carried by an experimental strain of Listeria monocytogenes. After 7 days of infection, both types of mice showed equivalent expansion and activity of antigen-specific CD8 effector T cells. But mice with a defect in CD4 T cells generated much weaker secondary responses, characterized by the presence of far fewer expanding memory CD8 T cells after a secondary challenge. These results imply a role for CD4 T cells either in the initial programming of CD8 T cells or during the secondary memory response.
Further experiments suggest that this CD4 T-cell help is necessary for the initial programming of naive CD8 T cells. Memory CD8 T cells that developed in the absence of CD4 help were transferred into wild-type mice. After transfer, the recipient mice were challenged again, whereupon the CD8 T cells showed a reduced ability to proliferate even though the recipient mice expressed MHC class II. This result indicates that CD4 T-cell help is required during the priming of CD8 T cells and not simply at the time of secondary responses.