Thymic epitope expression determines pattern of CD4 T cell peripheral tolerance

A few months ago I posted my analysis of one of the important papers from journal of Immunity discussing mechanisms of CD4 T cell peripheral tolerance. In that paper, the authors led by J.J. Moon, showed that number and functionality of CRE recombinase-specific endogenous CD4 T cells were determined by antigen expression in the thymus. 

Today, journal Nature Immunology published very similar study from Marc Jenkins' lab (JJ Moon's former supervisor) where the authors showed that number and functionality of eGFP epitope-specific endogenous CD4 T cells were also determined by level of specific epitope expression in the thymus. These studies have important implications predicting the efficacy of vaccines and mechanisms of autoimmune diseases, so lets review it.

As some of you might know Marc Jenkins' lab pioneered technique for analysis of endogenous antigen[epitope]-specific T cells in WT mice. Here, the authors have analysed expansion of endogenous eGFP epitope:MHC II tetramer⁺ CD4 T cells in dozen of transgenic mice expressing eGFP protein under the guidance of different ubiquitous or tissue-specific promoters. 

This analysis revealed 3 patterns of T cell tolerance: ignorance, thymic Treg development and thymic deletion. Mechanistically, level of antigen expression in the thymus determined which out of these 3 tolerance patterns were operational.   

Tolerance by ignorance: Ins1^eGFP mice express eGFP exclusively in pancreas. Analysis showed that both Ins1^eGFP  and WT mice harbor similar number of eGFP-specific naive CD4 T cells, implying ignorance.

Tolerance by Treg induction: Ins2^eGFP mice express eGFP in pancreas and in the thymus in a AIRE-dependent manner.

Presence of eGFP in the thymus in Ins2^eGFP mice slightly reduced tet⁺ CD4 T cell numbers and correspondingly increased frequency of tet⁺ Foxp3⁺ CD4 T cells. 

Immunization with CFA-eGFP peptide showed that tolerance in Ins2^eGFP mice depended on AIRE-driven eGFP epitope expression in the thymus.

Tolerance by thymic deletion: UBC^eGFP mice displayed a profound thymic deletion of eGFP-specific tet⁺ CD4 T cells. 

The authors clearly showed that eGFP expression in the thymus inversely correlated with the number of tet⁺ CD4 T cells. 

Similar pattern of T cell "tolerance" were found for truly nonself- and self-epitope-specific T cells.

In summary, this study confirmed that level of antigen expression in the thymus (and not in periphery) determined overall T cell tolerance status. By analyzing the number of antigen-specific human T cells [in comparison to reference "self"-specific T cell numbers] the scientist could predict efficacy of vaccines, tumor vaccine for example, or predict the potential for development of autoimmune diseases.

David Usharauli