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CD45RC isoforms define two types of CD4 memory T cells, one of which depends on persisting antigen.

Bunce C, Bell EB - J. Exp. Med. (1997)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Immunology Research Group, Biological Sciences, University of Manchester, United Kingdom.

ABSTRACT
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.

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Antigen-experienced CD45RC−  CD4 T cells that transfer a DNCB-specific  DTH response revert completely to CD45RC+  in nude recipients, a change that was inhibited  by residual antigen. CD45RC− CD4 T cells  were purified from TDL of rats sensitized 4 d  before with DNCB and adoptively transferred  into intermediate nude recipients. TDL were recovered (a) 2 mo later (left protocol) or (b) 7 mo  later from DNCB ear-challenged intermediate  nude rats (right protocol), separated into CD45RC+  revertants and CD45RC− CD4 T cells and  transferred (10 × 106 cells/recipient) into secondary nude rats. These were sensitized with  DNCB after 3 wk and ear-challenged 4 d later.  Ear thickness was measured after 24 h. Histograms are means ± SD of 4, 4, 2, 4, and 4 (left to  right) rats per group. Test of significance: (a)  control vs CD45RC+, P <0.001; CD45RC+  vs CD45RC−, P       <0.01; (b) CD45RC+ vs  CD45RC−, P <0.01.
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Figure 3: Antigen-experienced CD45RC− CD4 T cells that transfer a DNCB-specific DTH response revert completely to CD45RC+ in nude recipients, a change that was inhibited by residual antigen. CD45RC− CD4 T cells were purified from TDL of rats sensitized 4 d before with DNCB and adoptively transferred into intermediate nude recipients. TDL were recovered (a) 2 mo later (left protocol) or (b) 7 mo later from DNCB ear-challenged intermediate nude rats (right protocol), separated into CD45RC+ revertants and CD45RC− CD4 T cells and transferred (10 × 106 cells/recipient) into secondary nude rats. These were sensitized with DNCB after 3 wk and ear-challenged 4 d later. Ear thickness was measured after 24 h. Histograms are means ± SD of 4, 4, 2, 4, and 4 (left to right) rats per group. Test of significance: (a) control vs CD45RC+, P <0.001; CD45RC+ vs CD45RC−, P       <0.01; (b) CD45RC+ vs CD45RC−, P <0.01.

Mentions: To investigate more conclusively whether antigen-experienced memory T cells can revert from CD45RC− to RC+, highly purified CD45RC− CD4 T cells (>98.0% pure) from 4-d sensitized rats were “parked” in athymic nude recipients until retransfer (Fig. 3, left protocol). Approximately 60% of the donor-derived population (carrying the RT7b allotype marker) subsequently re-expressed the high molecular weight isoform (CD45RC+) (e.g., 34, 35). Donor-derived CD45RC+ revertants and CD45RC− CD4 T cells were recovered from TDL of the intermediate nude rats after 2 mo, purified and re-transferred to secondary nude recipients. Surprisingly, the DNCB-specific response was contained entirely within the CD45RC+ subset (Fig. 3 a). No specific DTH activity remained within the CD45RC− subset; an equal number of retransferred CD45RC− CD4 T cells gave a response that was indistinguishable from the negative control. Clearly antigen-specific memory T cells survived in the complete absence of antigen, but all expressed the CD45RC+ phenotype.


CD45RC isoforms define two types of CD4 memory T cells, one of which depends on persisting antigen.

Bunce C, Bell EB - J. Exp. Med. (1997)

Antigen-experienced CD45RC−  CD4 T cells that transfer a DNCB-specific  DTH response revert completely to CD45RC+  in nude recipients, a change that was inhibited  by residual antigen. CD45RC− CD4 T cells  were purified from TDL of rats sensitized 4 d  before with DNCB and adoptively transferred  into intermediate nude recipients. TDL were recovered (a) 2 mo later (left protocol) or (b) 7 mo  later from DNCB ear-challenged intermediate  nude rats (right protocol), separated into CD45RC+  revertants and CD45RC− CD4 T cells and  transferred (10 × 106 cells/recipient) into secondary nude rats. These were sensitized with  DNCB after 3 wk and ear-challenged 4 d later.  Ear thickness was measured after 24 h. Histograms are means ± SD of 4, 4, 2, 4, and 4 (left to  right) rats per group. Test of significance: (a)  control vs CD45RC+, P <0.001; CD45RC+  vs CD45RC−, P       <0.01; (b) CD45RC+ vs  CD45RC−, P <0.01.
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Figure 3: Antigen-experienced CD45RC− CD4 T cells that transfer a DNCB-specific DTH response revert completely to CD45RC+ in nude recipients, a change that was inhibited by residual antigen. CD45RC− CD4 T cells were purified from TDL of rats sensitized 4 d before with DNCB and adoptively transferred into intermediate nude recipients. TDL were recovered (a) 2 mo later (left protocol) or (b) 7 mo later from DNCB ear-challenged intermediate nude rats (right protocol), separated into CD45RC+ revertants and CD45RC− CD4 T cells and transferred (10 × 106 cells/recipient) into secondary nude rats. These were sensitized with DNCB after 3 wk and ear-challenged 4 d later. Ear thickness was measured after 24 h. Histograms are means ± SD of 4, 4, 2, 4, and 4 (left to right) rats per group. Test of significance: (a) control vs CD45RC+, P <0.001; CD45RC+ vs CD45RC−, P       <0.01; (b) CD45RC+ vs CD45RC−, P <0.01.
Mentions: To investigate more conclusively whether antigen-experienced memory T cells can revert from CD45RC− to RC+, highly purified CD45RC− CD4 T cells (>98.0% pure) from 4-d sensitized rats were “parked” in athymic nude recipients until retransfer (Fig. 3, left protocol). Approximately 60% of the donor-derived population (carrying the RT7b allotype marker) subsequently re-expressed the high molecular weight isoform (CD45RC+) (e.g., 34, 35). Donor-derived CD45RC+ revertants and CD45RC− CD4 T cells were recovered from TDL of the intermediate nude rats after 2 mo, purified and re-transferred to secondary nude recipients. Surprisingly, the DNCB-specific response was contained entirely within the CD45RC+ subset (Fig. 3 a). No specific DTH activity remained within the CD45RC− subset; an equal number of retransferred CD45RC− CD4 T cells gave a response that was indistinguishable from the negative control. Clearly antigen-specific memory T cells survived in the complete absence of antigen, but all expressed the CD45RC+ phenotype.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Immunology Research Group, Biological Sciences, University of Manchester, United Kingdom.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus