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Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105
The properties of a self-specific T cell’s TCR that determine its pathogenicity are not well understood. We developed TCR retroviral transgenic, or retrogenic, models of myelin oligodendroglial glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) to compare the pathologic potential of five H-2 Ab/MOG35–55-specific TCRs. The TCRs were cloned and retrovirally transduced into either TCR
β-deficient hybridoma cells or Rag1–/– bone marrow progenitor cells. Comparison of the hybridomas, identical except for TCR sequence, revealed distinct responsiveness, or functionally determined affinity, for cognate Ag. Retrogenic mice were produced by transfer of transduced progenitor cells into Rag1–/– recipients. T cells were detected within 4 wk. Engraftment levels varied considerably among the different TCRs and showed separate variability among individual mice. T cells were predominantly naive and virtually exclusively CD4+ and CD25–. Relative responses of the retrogenic T cells to Ag paralleled those of the hybridoma cells. Induction of EAE through active immunization led to rapid and severe disease in all mice expressing MOG-specific TCR. The mice additionally developed spontaneous disease, the incidence of which varied with the individual receptors. Interestingly, spontaneous disease frequency and intensity could not be correlated with the functional affinity of the respective TCR. Instead, it was associated with engraftment level, even when measured weeks before the onset of disease symptoms. Our results demonstrate the feasibility of using retrogenic modeling to compare TCRs in the EAE system. They further suggest that affinity is not a primary determinant in spontaneous EAE development in mice expressing monotypic TCRs and that autoreactive T cell frequency is of greater significance.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant R01 AI056153 (to T.L.G.) and by the American Lebanese Syrian Associated Charities/St. Jude Children’s Research Hospital.
2 Address correspondence and reprint requests to Dr. Terrence L. Geiger, Associate Member, Department of Pathology, St. Jude Children’s Research Hospital, 332 North Lauderdale, D-4047, Memphis, TN 38105. E-mail address: terrence.geiger{at}stjude.org
3 Abbreviations used in this paper: MBP, myelin basic protein; CFP, cyan fluorescent protein; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendroglial glycoprotein; MSCV, murine stem cell virus; Tg, transgenic.
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