Microchimerism maintains deletion of the donor cell–specific CD8+ T cell repertoire
Weldy V. Bonilla, Markus B. Geuking, Peter Aichele, Burkhard Ludewig, Hans Hengartner, Rolf M. Zinkernagel
Weldy V. Bonilla, Markus B. Geuking, Peter Aichele, Burkhard Ludewig, Hans Hengartner, Rolf M. Zinkernagel
View: Text | PDF
Research Article Immunology

Microchimerism maintains deletion of the donor cell–specific CD8+ T cell repertoire

Abstract

Rare cases of stable allograft acceptance after discontinuation of immunosuppression are often accompanied by macrochimerism (> 1% donor cells in blood) or microchimerism (< 1% donor cells in blood). Here, we have investigated whether persistence of donor cells is the cause or the consequence of long-lasting CTL unresponsiveness. We found that engraftment of splenocytes bearing a single foreign MHC class I–restricted epitope resulted in lifelong donor cell microchimerism and specific CTL unresponsiveness. This status was reversed in a strictly time- and thymus-dependent fashion when the engrafted cells were experimentally removed. The results presented herein show that microchimerism actively maintains CTL unresponsiveness toward a minor histocompatibility antigen by deleting the specific repertoire and thus excluding dominant, T cell extrinsic mechanisms of CTL unresponsiveness independent of systemically persisting donor cell antigen.

Authors

Weldy V. Bonilla, Markus B. Geuking, Peter Aichele, Burkhard Ludewig, Hans Hengartner, Rolf M. Zinkernagel

×

Figure 4

Thymus- and time-dependent reemergence of antigen-specific CTL precursors after removal of H8 donor cells.

Options: View larger image (or click on image) Download as PowerPoint
Thymus- and time-dependent reemergence of antigen-specific CTL precursor...
(A) Sex-matched H8 splenocytes were transferred to B6 recipients. Chimerism was either allowed to persist or was terminated at the indicated time point by transfer of d10-LCMV-F1 splenocytes. Forty-two or 35 days after termination of H8 chimerism, i.e., on day 70 or 735 after initial H8 cell transfer, respectively, mice were challenged with LCMV. Specific CTL activity was measured 8 days after infection in a primary ex vivo CTL assay on GP33-coated (filled circles), NP396-coated (filled triangles), and uncoated (open circles) EL-4 target cells. Effector and target cells were incubated for 5 hours (day 70) or 20 hours (day 735). The longer incubation time of 20 hours was necessary to detect the lower response in these old mice. Each line represents an individual mouse. (B) MHC class I H-2DbGP33 tetramer binding and GP33-specific IFN-γ production on gated CD8+ cells from the same mice as in A after LCMV challenge on day 735. (C) Four weeks after transfer of H8 splenocytes into euthymic or thymectomized recipients, chimerism was eliminated in all animals by an additional transfer of d10-LCMV-F1 splenocytes. At 14 or 42 days after this second transfer, mice were infected with LCMV. GP33-specific (filled circles) and NP396-specific (filled triangles) CTL activities were measured 8 days later in a standard primary ex vivo CTL assay on peptide-coated or noncoated (open circles) EL-4 target cells. One representative experiment of 3 is shown.