Yesterday journal Immunity published an important paper about mechanisms of immune tolerance. This study showed that peripheral immune tolerance, as we knew it, doesn't really exist. Here is my analysis of main findings from this study.
The authors have used 4 types of mouse strains for this study, each of them expressing nominal neo-self protein, Cre recombinase, under the guidance of ubiquitous or tissue-specific promoters (UBC-Cre (everywhere), RIP-Cre (insulin producing cells), CC10-Cre (lung tissue), Vil-Cre (intestine tissue). To track endogenous Cre:I-Abspecific CD4 T cells the authors designed CD4 T cell Cre [pp61-71]:I-Ab tetramers. Staining for Cre:I-Ab tetramer positive CD4 T cells revealed that all strains, except UBC-Cre mice, harbored equal number of Cre:I-Ab specific CD4 T cells.
To test the functionality of Cre:I-Ab tetramer positive CD4 T cells mice were immunized with Cre peptide/CFA. Both WT and RIP-Cre mice showed similar expansion of Cre:I-Ab tetramer positive CD4 T cells. UBC-Cre mice showed minimal expansion as expected [due to low frequency]. Interestingly, expansion of Cre:I-Ab tetramer positive CD4 T cells from CC10-Cre and Vil-Cre were minimal too, even though these mice harbored similar frequency of Cre:I-Ab tetramer positive CD4 T cells as WT or RIP-Cre mice.
These results suggested that in CC10-Cre and Vil-Cre mice Cre:I-Ab tetramer positive CD4 T cells were actively "contained". Indeed, CC10-Cre and Vil-Cre mice harbored large proportion of Cre:I-Ab tetramer positive Foxp3+ CD4 T cells
and depletion of Foxp3+ CD4 T cells in these mice [but not in WT, RIP-Cre or UBC-Cre mice] allowed further expansion of Foxp3-negative Cre:I-Ab tetramer positive CD4 T cells upon Cre peptide/CFA immunization.
Additional experiments revealed that development of Cre:I-Ab tetramer positive Foxp3+ CD4 T cells were not affected in Foxp3ΔCNS1 BM chimera mice, implying that Cre:I-Ab tetramer positive Foxp3+ CD4 T cells were mostly thymic Foxp3+ CD4 T cells.
However, peripheral antigen expression promoted tonic signaling and active cycling of Cre:I-Ab tetramer positive Foxp3+ CD4 T cells in CC10-Cre and Vil-Cre mice.
Finally, the authors showed that multiple immunization [Lm-Cre infection followed by Cre/CFA immunization] was able to overcome Foxp3+ CD4 T cell-mediated non-deletional tolerance in RIP-Cre, CC10-Cre and Vil-Cre mice [but not in UBC-Cre mice] that resulted in antigen-specific tissue retention of Cre:I-Ab tetramer positive CD4 T cells and could even induce a transient increase in blood glucose level in RIP-Cre mice [though none of these mice showed any overt sustained autoimmunity].
In summary, these results indicate that (a) peripheral tolerance is primarily maintained by non-deletional action of thymus derived Foxp3+ CD4 T cells, and (b) without ectopic expression of peripheral antigen in the thymus [via Aire or Fezl], such non-deletional tolerance could be easily breached by recurrent infection resulting in sustained autoimmunity.
David Usharauli
To test the functionality of Cre:I-Ab tetramer positive CD4 T cells mice were immunized with Cre peptide/CFA. Both WT and RIP-Cre mice showed similar expansion of Cre:I-Ab tetramer positive CD4 T cells. UBC-Cre mice showed minimal expansion as expected [due to low frequency]. Interestingly, expansion of Cre:I-Ab tetramer positive CD4 T cells from CC10-Cre and Vil-Cre were minimal too, even though these mice harbored similar frequency of Cre:I-Ab tetramer positive CD4 T cells as WT or RIP-Cre mice.
These results suggested that in CC10-Cre and Vil-Cre mice Cre:I-Ab tetramer positive CD4 T cells were actively "contained". Indeed, CC10-Cre and Vil-Cre mice harbored large proportion of Cre:I-Ab tetramer positive Foxp3+ CD4 T cells
and depletion of Foxp3+ CD4 T cells in these mice [but not in WT, RIP-Cre or UBC-Cre mice] allowed further expansion of Foxp3-negative Cre:I-Ab tetramer positive CD4 T cells upon Cre peptide/CFA immunization.
Additional experiments revealed that development of Cre:I-Ab tetramer positive Foxp3+ CD4 T cells were not affected in Foxp3ΔCNS1 BM chimera mice, implying that Cre:I-Ab tetramer positive Foxp3+ CD4 T cells were mostly thymic Foxp3+ CD4 T cells.
However, peripheral antigen expression promoted tonic signaling and active cycling of Cre:I-Ab tetramer positive Foxp3+ CD4 T cells in CC10-Cre and Vil-Cre mice.
Finally, the authors showed that multiple immunization [Lm-Cre infection followed by Cre/CFA immunization] was able to overcome Foxp3+ CD4 T cell-mediated non-deletional tolerance in RIP-Cre, CC10-Cre and Vil-Cre mice [but not in UBC-Cre mice] that resulted in antigen-specific tissue retention of Cre:I-Ab tetramer positive CD4 T cells and could even induce a transient increase in blood glucose level in RIP-Cre mice [though none of these mice showed any overt sustained autoimmunity].
In summary, these results indicate that (a) peripheral tolerance is primarily maintained by non-deletional action of thymus derived Foxp3+ CD4 T cells, and (b) without ectopic expression of peripheral antigen in the thymus [via Aire or Fezl], such non-deletional tolerance could be easily breached by recurrent infection resulting in sustained autoimmunity.
David Usharauli
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