Immune regulation in self tolerance: functional elimination of a self‐reactive, counterregulatory CD8⁺ T lymphocyte circuit by neonatal transfer of encephalitogenic CD4⁺ T cells lines

Abstract

Transfer of encephalitogenic, CD4+ T lymphocyte lines into syngeneic adult Lewis rats not only leads to the development of experimental autoimmune encephalomyelitis (EAE), but, in addition, to the expansion of counterregulatory, CD8+ T lymphocyte clones which are able to lyse specifically the encephalitogenic T cells in vitro and to neutralize their encephalitogenic capacity in vivo. In striking contrast, in neonatal rats, which still lack myelin (autoantigens), injection of the same encephalitogenic lines neither mediates EAE, nor confers protection in later life against the myelin-specific T cells. In fact, this treatment results in the life-long functional elimination of counterregulatory, clonotypic CD8+ T lymphocytes, which cannot even be reinduced by repeated injections of the relevant CD4+ T line. These data seem to point to a self-protective T cell control mechanism which is developed within the immune system prior to, and thus independent of the appearance of the appropriate self antigen.

Autoimmune CD4+ T Cell Memory: Lifelong Persistence of Encephalitogenic T Cell Clones in Healthy Immune Repertoires

“…In the mouse, CD8 ϩ (44,45). This mechanism is not effective in our system, because transfer of encephalitogenic T cells into neonatal recipients fails to recruit protective CD8 ϩ T cells (19). Another regulatory loop which has resurfaced recently is CD4 ϩ CD25 ϩ regulatory T cells, which down-regulate the pathogenic potential of autoreactive cells in vivo and in vitro via membrane-dependent contacts (46,47).…”

“…Although the GFPlabeled T cells produce a foreign protein which would cause their eventual rejection in adults, the cells are tolerated lifelong after transfer into neonatal hosts. Our model is based on previous work which had established that encephalitogenic T cells transferred into neonatal hosts neither induce EAE nor activate counterregulatory T cell loops (18,19). Instead, the inoculated T cells persist in the recipients' immune organs throughout life (29).…”

“…T MBP-GFP cells transferred clinical disease to adult animals, which in course and severity was indistinguishable from EAE transferred by their non-manipulated counterparts. However, neither of the MBP-specific T cells attacked newborn recipients (18,19).…”

Gene transfer into CD4+ T lymphocytes: Green fluorescent protein-engineered, encephalitogenic T cells illuminate brain autoimmune responses

“…toxic CD8 + host T cells, a response that could well be triggered in adult rats by the genetically modified, GFP-expressing T-cell lines 9 . Therefore, to assess the long-term persistence of GFP-expressing cells in the immune organs of immunologically uncompromised healthy rats, we induced tolerance by the adoptive transfer of T MBP GFP cells into neonatal rats 24 hours postpartum.…”

Experimental autoimmune encephalomyelitis: Cytokines, effector t cells, and antigen-presenting cells in a prototypical th1-mediated autoimmune disease

“…In an independent study, in vivo depletion of CD8+ cells following the first exacerbation of EAE raised susceptibility to subsequent relapses [14]. Consistent with these findings, the EAE literature from the 1980s and early 1990s is inundated with manuscripts describing CD8+ "suppressor" T cells (frequently designated Ts cells), capable of inhibiting EAE induced by the adoptive transfer of myelin-reactive CD4+ T cells [15][16][17]. Such Ts cells were generally generated by "inoculating" mice with inactivated or "subclinical" doses of encephalitogenic CD4+ T cell lines or clones.…”