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
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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

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Figure 2

H8 chimerism-induced antigen-specific CTL unresponsiveness.

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H8 chimerism-induced antigen-specific CTL unresponsiveness. (A–D) Sex-ma...
(A–D) Sex-matched H8 splenocytes were adoptively transferred to B6 mice. At the indicated time points (A) or 28 days after transfer (C and D), recipient and control mice without cell transfer were infected with LCMV. (A) At 8 to 9 days after infection with LCMV, splenocytes were tested for GP33-specific (filled circles) and NP396-specific (filled triangles) CTL activity in a standard primary ex vivo CTL assay. Uncoated EL-4 target cells (open circles) are shown at the highest effector to target ratio. Each line represents an individual mouse. One representative experiment of 3 (day 45) or 2 (day 300) is shown. (B) DNA was isolated from blood samples taken from chimeric recipients on days 45 and 300 as shown in Figure 2A. The presence of H8 chimerism was confirmed by H8-specific PCR analysis. (C) Frequencies of GP33- and NP396-specific CD8+ T cells in spleen 8 days after LCMV infection were enumerated using MHC class I H-2DbGP33 (black bars) and H-2DbNP396 (white bars) tetramers. (D) Splenocytes from the same mice as in C were tested for IFN-γ production upon restimulation with GP33 or NP396 or without restimulation. Representative FACS plots are shown, and bars indicate the mean ± SD of 3 mice (C and D).