Spontaneous breakdown of T cell tolerance in the mouse lgG2a^b-suppression model despite long-term tolerogenesis since the perinatal period

Abstract

T cell-induced IgG2ab allotype suppression provides a physiological model for the study of T cell responsiveness or tolerance to this Ig allotype. Normal, untreated mice of the Igha haplotype possess a basic and easily amplifiable T cell reactivity against the expression of IgG2ab, while their Ighb congenic mice produce substantial levels of this Ig and thereby are tolerant to this self-protein antigen. Therefore, the involved TCR repertoire in Igha and Ighb congenic mice is different. We have previously shown, in Ighb and Igha/b mice perinatally deprived of IgG2ab expression, that T lymphocytes bearing anti-IgG2ab TCR can emerge and induce an autoimmune suppression of IgG2ab. Correlatively, full and IgG2ab-specific T cell tolerance can be induced in Igha mice by their perinatal exposure to this Ig allotype. In this physiological model, which involves neither superantigens nor TCR-transgenic T cells, the responsive or tolerant state in Igha mice is assessed in vivo by the capacity to induce or not a T CD8(+)-dependent suppression of IgG2ab allotype production in Igha/b recipients of these cells. Taking advantage of this system, we were able to demonstrate here that, over the long term, this perinatally induced, IgG2ab-specific T cell tolerance was not definitively acquired, and that a spontaneous and total tolerance breakdown was observed by the age of 6 months. Furthermore, we showed that perinatal followed by prolonged tolerogen treatments up to 3, 6 and even 9 months of age were no longer sufficient to assure definitive T cell tolerance acquisition to IgG2ab, as the T cell suppression-induction capacity of Igha mice was partially and then entirely restored 3-6 months after the end of the tolerogen administration.

Central tolerance induction in natural immunoglobulin-allotype-specific T cells

“…Exposure of adult Igh a/a mice to soluble IgG 2a b can induce in some of them transient T cell tolerance to this Ig allotype [20]. Because IgG 2a b -containing thymi from Igh b/b adults were able to induce full unresponsiveness to IgG 2a b in their Igh a/a nu/nu hosts, we examined the tolerance-induction capacities of thymi from Igh a/a adults, treated with soluble IgG 2a b for 6 weeks prior to use.…”

“…This tolerance induction is not due to either the establishment of a reversible state of anergy or to the recruitment of dominant regulatory T cells, but rather to physical elimination of anti-IgG 2a b T cells or their irreversible inactivation. This state of full T cell unresponsiveness reverts spontaneously with tolerogen clearance, even when long-term tolerogenesis is chronically exerted from the perinatal period until the age of 9 months [20]. De novo emergence of anti-IgG 2a b T cells in Igh a/a thymi, still functional at 9 months of age, is responsible for the tolerance breakdown [21].…”

Breakdown of T cell tolerance to IgG2ab in Igha mice by de novo emerging anti-IgG2ab T cells and not anergy reversion

“…(ii) Anti-H-Y IgG2a b administration. Furthermore, the acquired tolerance was not definitive, even when the exposure to tolerogen was TCR transgenic CD8 ϩ T cells, anergized in male nu/nu recipients by a TCR-CD8 down-regulation mechanism (37), prolonged to 9 months of age (11). Here, we shed some light on the mechanisms of induction and reversion of this regained in vivo proliferative capacity when parked for 8 weeks in syngenic nu/nu females (38).…”

“…Conversely, perinatal exposure of Igh a mice to the soluble form of IgG2a b allotype (but not to irrelevant Ig) induced full In this Ig-allotype-suppression system, cellular collaboration between the donor's anti-IgG2a b CD4 ϩ and CD8 ϩ T cells is and specific tolerance to this allotype (10). In Igh a mice, T cell tolerance to IgG2a b is characterized in vivo by the required during the suppression-induction phase (5,6) but incapacity of the IgG2a b -primed T splenocytes to induce detection and quantification have been fully described elsewhere (11). Briefly, the presence of serum IgG2a b was first IgG2a b suppression in Igh a/b recipients.…”

“…We recently examined in detail the maintenance of this tolerance and showed that determined by immunoprecipitation in 1% agar-gel medium using a BALB/c anti-IgG2a b serum with a detection limit of this total unresponsiveness was, however, not definitively acquired but progressively reversed after IgG2a b clearance 5 µg/ml. The IgG2a b concentration was then measured, using anti-IgG2a b 5.7.2 mAb (27), in an ELISA with a detection limit (11). Even when Igh a mice were continuously exposed to the tolerogen from the perinatal period to 3 or 6 months of age, of 0.05 µg/ml.…”