Graded Deletion and Virus-Induced Activation of Autoreactive CD4+ T Cells

Abstract

We have examined factors governing the negative selection of autoreactive CD4+ T cells in transgenic mice expressing low (HA12 mice) vs high (HA104 mice) amounts of the influenza virus hemagglutinin (HA). When mated with TS1 mice that express a transgenic TCR specific for the I-Ed-restricted determinant site 1 (S1) of HA, thymocytes expressing high levels of the clonotypic TCR were deleted in both HA-transgenic lineages. However, through allelic inclusion, thymocytes with lower levels of the clonotypic TCR evaded deletion in TS1 × HA12 and TS1 × HA104 mice to graded degrees. Moreover, in both lineages, peripheral CD4+ T cells could be activated by the S1 peptide in vitro, and by influenza virus in vivo. These findings indicate that allelic inclusion can allow autoreactive CD4+ thymocytes to evade thymic deletion to varying extents reflecting variation in the expression of the self peptide, and can provide a basis for the activation of autoreactive peripheral T cells by viruses bearing homologues of self peptides (“molecular mimicry”).

CD25+ Immunoregulatory CD4 T Cells Mediate Acquired Central Transplantation Tolerance

“…HA104 mice express high levels of the HA Ag in all tissues whereas HA28 mice have been found to express lower levels. When TS1 mice are crossed with HA104 mice, the resulting double transgenic progeny delete the majority of all 6.5-expressing thymocytes (25). In contrast, (TS1 ϫ HA28)F 1 mice delete few of these cells, and rather have a peripheral repertoire characterized by large numbers of 6.5 ϩ CD4 T cells with an immunoregulatory phenotype (CD25 ϩ CD45RB int ) (20).…”

“…In addition, thymic self-tolerance in TS1 mice expressing HA as a "neo-self Ag" has been extensively studied (20,24,25) and has revealed the participation of multiple pathways of self-tolerance, including the development of CD4 ϩ CD25 ϩ T cells that demonstrate potent immunoregulatory activity. We hypothesized that such a population of immunoregulatory cells might also contribute to the tolerant state induced by central Ag exposure via intrathymic injection of Ag and may provide a valuable component of protocols designed to achieve transplantation tolerance.…”

CD4+ CD25+ Regulatory T Cell Repertoire Formation in Response to Varying Expression of a neo-Self-Antigen

“…However, thymocytes can also undergo deletion in response to selfpeptides (28,(32)(33)(34)(35)(36) and the relationship between CD25 ϩ T cell selection and deletion of autoreactive thymocytes remains poorly understood. In the studies here, TS1x␤-myoHA mice were found to contain significantly fewer 6.5 high CD4 SP thymocytes than TS1xPevHA and TS1xHA28 mice, although in all cases similar percentages (ϳ30%) were CD25…”

“…In particular, we wanted to exclude the possibility that enhanced deletion of thymocytes expressing high levels of the 6.5 TCR caused the residual 6.5 high CD4 SP thymocytes in TS1x␤-myoHA mice to contain elevated numbers of CD25 ϩ thymocytes that coexpressed endogenous TCR ␣-chains (4,16,28). Accordingly, additional chimeras were generated using BM obtained from TS1.RAG mice and irradiated ␤-myoHA and BALB/c recipients.…”

Hilary Koprowski and the Viral Immunity Hub at the 1980s Wistar Institute: A T Cell Epitope Perspective

“…Andy Caton, who came from England to join the Gerhard group, created transgenes of a T cell receptor that recognizes the HA 111-119 epitope, leading to establishment of a powerful system to study self-T cell responses. (13) Laurence ''Ike'' Eisenlohr based his doctoral research, performed in my lab at Wistar, and many excellent discoveries in his career, on understanding the mechanism by which these distinct influenza helper T cell epitopes are presented to T cells. (14) I am indebted to Hilary Koprowski for his vision, and to Walter Gerhard and the ''braintrust'' of all of our Wistar colleagues in viral immunology for their insightful, intelligent, and critical discussions and for their helping hands that channeled this research along a pathway that continues to pay dividends.…”