CD45RC Isoforms Define Two Types of CD4 Memory T Cells, One of which Depends on Persisting Antigen

The cellular basis of immunological memory remains a controversial area with respect to the identity of memory T cells and the role of persisting antigen. CD4 T cells are phenotypically divided by the expression of high and low molecular weight isoforms of CD45, surface markers that are frequently used to identify "naive" (CD45Rhigh) and "memory" (CD45Rlow) subsets. The latter subset responds rapidly in antigen recall assays but paradoxically has a short life span, a property that is difficult to reconcile with long-term memory. The present study examines these issues using a DTH (delayed-type hypersensitivity) model in which contact sensitivity to dinitrochlorobenzene (DNCB) was transferred to athymic nude rats by recirculating CD4 T cell subsets defined in the rat by the anti-CD45RC mAb OX22. As expected, CD45RC+ (but not RC-) CD4 T cells from normal unprimed rats transferred a DNCB-specific DTH response, whereas, 4 d after sensitization the CD45RC- (memory) subset alone contained the DNCB reactivity. However, when donor cells were collected from thymectomized rats sensitized two mo earlier, DNCB-specific responses were transferred by both CD45RC- and RC+ subsets suggesting that many of the latter had developed from cells with a memory phenotype. This was confirmed when CD45RC CD4 T cells from 4-d primed rats were parked in intermediate nude recipients and recovered 2 mo later. DNCB-specific activity was now found wholly within the CD45RC+ "revertant" subset; the CD45RC-CD4 T cell population was devoid of activity. Importantly, we found that the total switch-back from CD45RC- to RC+ could be prevented, apparently by persisting antigen. The results indicate that there are two functionally distinct categories of memory T cells: one, a short-lived CD45Rlow type which orchestrates the rapid kinetics, the other, a longer-lived CD45Rhigh revertant which ensures that immunological memory endures.