Thymic Selection of the TCell Repertoire

Random gene rearrangement within TCR germ-line DNA combined with junctional diversity can generate an enormous TCR repertoire, with an estimated potential diversity exceeding 1015 for the ap receptor and 1018 for the 78 receptor. Gene products encoded by the rearranged TCR genes have no inherent affinity for foreign antigen plus a self-MHC molecule; they theoretically should be capable of recognizing soluble antigen (either foreign or self), self-MHC molecules, or

antigen plus a nonself-MHC molecule. Nonetheless, the most distinctive property of mature T cells is that they recognize only foreign antigen combined with self-MHC molecules.

As noted, thymocytes undergo two selection processes in the thymus:

■ Positive selection for thymocytes bearing receptors capable of binding self-MHC molecules, which results in MHC restriction. Cells that fail positive selection are eliminated within the thymus by apoptosis.

■ Negative selection that eliminates thymocytes bearing high-affinity receptors for self-MHC molecules alone or self-antigen presented by self-MHC, which results in self-tolerance.

Both processes are necessary to generate mature T cells that are self-MHC restricted and self-tolerant. As noted already, some 98% or more of all thymocytes die by apoptosis within the thymus. The bulk of this high death rate appears to reflect a weeding out of thymocytes that fail positive selection because their receptors do not specifically recognize foreign antigen plus self-MHC molecules.

Early evidence for the role of the thymus in selection of the T-cell repertoire came from chimeric mouse experiments by R. M. Zinkernagel and his colleagues (Figure 10-4). These researchers implanted thymectomized and irradiated (A X B) F1 mice with a B-type thymus and then reconstituted the animal's immune system with an intravenous infusion of F1 bone-marrow cells. To be certain that the thymus graft did not contain any mature T cells, it was irradiated before being transplanted. In such an experimental system, T-cell progenitors from the (A X B) F1 bone-marrow transplant mature within a thymus that expresses only B-haplotype MHC molecules on its stromal cells. Would these (A X B) F1 T cells now be MHC-restricted for the haplotype of the thymus? To answer this question, the chimeric mice were infected with LCM virus and the immature T cells were then tested for their ability to kill LCM-infected target cells from the strain A or strain B mice. As shown in Figure 10-4, when TC cells from the chimeric mice were tested on LCM virus infected target cells from strain A or strain B mice, they could only lyse LCM-infected target cells from strain B mice. These mice have the same MHC haplotype, B, as the implanted thymus. Thus, the MHC haplotype of the thymus in which T cells develop determines their MHC restriction.

Thymic stromal cells, including epithelial cells, macrophages, and dendritic cells, play essential roles in positive and negative selection. These cells express class I MHC molecules and can display high levels of class II MHC also. The interaction of immature thymocytes that express the TCR-CD3 complex with populations of thymic stromal cells results in positive and negative selection by mechanisms that are under intense investigation. First, we'll examine the details of each selection process and then study some experiments that provide insights into the operation of these processes.

EXPERIMENT

@ Thymectomy @ Lethal x-irradiation si/

Strain-B thymus graft (H-2b) (A X B)F1 hematopoietic stem cells (H-2a/b)

Infect with LCM virus

Spleen cells

@ Thymectomy @ Lethal x-irradiation si/

Spleen cells

LCM-infected strain-A cells No killing

CONTROL

LCM-infected strain-B cells Killing

Infect with LCM virus

Infect with LCM virus

Spleen cells

LCM-infected strain-A cells Killing

FIGURE 10-4

LCM-infected strain-B cells Killing

Experimental demonstration that the thymus selects for maturation only those T cells whose T-cell receptors recognize antigen presented on target cells with the haplotype of the thymus. Thymectomized and lethally irradiated (A X B) F1 mice were grafted with a strain-B thymus and reconstituted with (A X B) F, bone-marrow cells. After infection with the LCM virus, the CTL cells were assayed for their ability to kill 51 Cr-labeled strain-A or strain-B target cells infected with the LCM virus. Only strain-B target cells were lysed, suggesting that the H-2fc grafted thymus had selected for maturation only those T cells that could recognize antigen combined with H-2fc MHC molecules.

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