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” (CD45R^high) and “memory” (CD45R^low) 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 CD45R^low type which orchestrates the rapid kinetics, the other, a longer-lived CD45R^high revertant which ensures that immunological memory endures.