General autoimmunity

Oral

Genetic vs. Selective Forces in Formation of the Human Thymic Tcr Repertoire

Friday, June 16
6:15 PM - 7:30 PM

Our knowledge about the formation of a TCR repertoire in the human thymus is limited. We used high throughput TCR sequencing to assess the degree of similarity of TCR repertoires of human thymocytes generated in human thymi of humanized mice generated with the same HSCs and autologous and allogeneic thymi. We observed that human thymus in humanized mice selects a very diverse TCR repertoire. Formation of the human TCR repertoire is largely stochastic and can be almost totally divergent in identical thymi generating thymocytes derived from the same pool of HSCs. We demonstrated the impact of thymic selection in narrowing the TCR repertoire. The proportion of overlapping CDR3βs was similar between identical and allogeneic thymi, showing that they may be cross-reactive and selected by different thymi or that there are shared epitopes that participate in selection in the context of different HLAs. We observed an increased overlap in β chains with higher frequencies. Length of more abundant CDR3βs decreased during thymic selection. CDR3β overlap was also detected between different SP cell populations, often with different Vβ gene usage. As the HLAs that SP CD4 and SP CD8 cells are selected on are different, the most likely explanation is that the shared CDR3βs are highly cross-reactive. We also showed that genetic background and thymic selection does not dramatically change the V and J gene usage in forming the TCR repertoire. Pairing of V and J genes is random and is only determined by the amount of expression of each gene.


 

Mohsen Khosravi Maharlooei

Columbia Center for Translational Immunology, Columbia University

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    Aleksandar Obradovic

    Columbia University

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      Markus Hoelzl

      Columbia Center for Translational Immunology, Columbia University

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        Robert Winchester

        Columbia University

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          Yufeng Shen

          Columbia University

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            Megan Sykes

            Columbia Center for Translational Immunology, Columbia University

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