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Frequency of Natural Regulatory CD4⁺CD25⁺ T Lymphocytes Determines the Outcome of Tolerance across Fully Mismatched MHC Barrier through Linked Recognition of Self and Allogeneic Stimuli¹

Rita Fucs^2,*, Joszilene T. Jesus^*, Paulo H. N. Souza Junior^*, Larissa Franco^*, Mauricio Verícimo^*, Maria Bellio and Alberto Nobrega^2,

^* Departamento de Immunobiologia, Instituto de Biologia, Universidade Federal Fluminense, Niteroi, Brasil; and Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil

We show in this study that long-term tolerance to allogeneic skin grafts can be established in the absence of immunosuppression by the combination of the following elements: 1) augmenting the frequency of regulatory CD4⁺CD25⁺ T cells (Treg) and 2) presentation of the allogeneic stimuli through linked recognition of allo- and self-epitopes on semiallogeneic F₁ APCs. BALB/c spleen cells enriched for CD4⁺CD25⁺ T lymphocytes were transferred either to BALB/c nu/nu mice or to BALB/c nu/nu previously injected with F₁(BALB/c x B6.Ba) spleen cells, or else grafted with F₁(BALB/c x B6.Ba) skin (chimeric BALB/c nu/nu-F₁). Chimeric BALB/c nu/nu-F₁ reconstituted with syngeneic CD25⁺-enriched spleen cells were unable to reject the previously transferred F₁(BALB/c x B6.Ba) spleen cells or F₁(BALB/c x B6.Ba) skin grafts, and a specific tolerance to a secondary B6 graft was obtained, with rejection of third-party CBA grafts. BALB/c nu/nu mice reconstituted only with syngeneic CD25⁺-enriched spleen cells rejected both B6 and CBA skin grafts. In contrast, when chimeric BALB/c nu/nu-F₁ were reconstituted with spleen populations comprising normal frequencies of Treg cells, the linked recognition of allo and self resulted in breaking of self tolerance and rejection of syngeneic grafts, strongly suggesting that linked recognition works in both directions, either to establish tolerance to allo, or to break tolerance to self, the critical parameter being the relative number of Treg cells.

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