Density dependent re-tuning of autoreactive T cells alleviates their pathogenicity in a lymphopenic environment
Autor: | Marilyn Augustine, Matthew E. Jung, Ronald H. Schwartz, Nevil J. Singh, Eleanore Chuang |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
CD4-Positive T-Lymphocytes T cell Immunology Cell Autoimmunity Biology Lymphocyte Activation Autoantigens Article 03 medical and health sciences Mice Antigen Negative feedback Lymphopenia medicine Immunology and Allergy Cytotoxic T cell Animals IL-2 receptor Cells Cultured Cell Proliferation Mice Knockout Peripheral Tolerance T-cell receptor CD28 Adoptive Transfer DNA-Binding Proteins Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Cytokines |
Popis: | Peripheral T cell tolerance is challenging to induce in partially lymphopenic hosts and this is relevant for clinical situations involving transplant tolerance. While the shortage of regulatory cells is thought to be one reason for this, T cell-intrinsic tolerance processes such as anergy are also poorly triggered in such hosts. In order to understand the latter, we used a T cell deficient mouse model system where adoptively transferred autoreactive T cells are significantly tolerized in a cell intrinsic fashion, without differentiation to regulatory T cells. Intriguingly these T cells often retain sufficient effector functions to trigger autoimmune pathology. Here we find that the high population density of the autoreactive T cells that accumulated in such a host limits the progression of the cell-intrinsic tolerance process in T cells. Accordingly, reducing the cell density during a second transfer allowed T cells to further tune down their responsiveness to antigenic stimulation. The retuning of T cells was reflected by a loss of the T cell’s abilities to proliferate, produces cytokines or help B cells. We further suggest, based on altering the levels of chronic antigen using miniosmotic pumps, that the effects of cell-density on T cell re-tuning may reflect the effective changes in the antigen dose perceived by individual T cells. This could proportionally elicit more negative feedback downstream of the TCR. Consistent with this, the retuned T cells showed signaling defects both proximal and distal to the TCR. Therefore, similar to the immunogenic activation of T cells, cell-intrinsic T cell tolerance may also involve a quantitative and progressive process of tuning down its antigen-responsiveness. The progress of such tuning seems to be stabilized at multiple intermediate stages by factors such as cell density, rather than just absolute antigen levels. |
Databáze: | OpenAIRE |
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