Activation-induced apoptosis of autoreactive and alloreactive T lymphocytes in the target organ as a major mechanism of tolerance
Abstract
Normal individuals have mature T lymphocytes that are capable of reacting to self‐antigens and can be activated by cross‐reacting environmental antigens. The mechanism that maintains immune tolerance and prevents these activated autoreactive T cells from causing autoimmune disease is unclear. We have previously hypothesized that activation‐induced apoptosis of previously activated autoreactive T cells in the target organ is a major mechanism for maintaining tolerance. Here I review the current evidence to support this hypothesis. It is proposed that when activated autoreactive T cells enter the target organ, they are reactivated mainly by non‐professional antigen‐presenting cells (APC) and deleted by activation‐induced apoptosis through the Fas (CD95) pathway before producing significant target organ damage. This apoptosis occurs because the reactivated T cells do not receive sufficient costimulation from the non‐professional APC to up‐regulate their expression of Bcl‐2‐related anti‐apoptotic proteins, which inhibit the CD95 pro‐apoptotic pathway. This is in contrast to the situation in peripheral lymphoid organs, where reactivation of T cells by professional APC results in sufficient costimulation‐induced up‐regulation of Bcl‐2‐related proteins to inhibit the CD95 pathway and allow T cell proliferation and survival as memory T cells. Activation‐induced apoptosis of alloreactive T cells in allografts can similarly account for spontaneous allograft acceptance, as occurs after MHC‐mismatched liver transplantation.
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Increased levels of gene expression resulting from higher vector doses promote immune tolerance through elevated expression of IL-10, enhanced apoptosis of effector T cells, and enhanced Treg induction.
“However, the exact opposite is true, and increased levels of gene expression resulting from higher vector doses promote immune tolerance through elevated expression of the immune suppressive cytokine IL-10, enhanced apoptosis of effector T cells, and enhanced Treg induction similar to that observed with a very high HBV inoculum in chimpanzees.15,56,57,58,59,60,61,62”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [61]
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- Authors
- Pender, M. P.
- Affiliations
- The University of Queensland (AU)
- Corresponding author
- Pender, Michael P
- ORCID
- Pender, Michael P
- Venue
- Immunology & Cell Biology
- Publisher
- Wiley
- Published
- 1999-06
- Volume
- 77
- Issue
- 3
- Pages
- 216-223
- ISSN
- 0004-945X (ISSN-L)
- 0818-9641
- 1440-1711
- OpenAlex
- W2077153831
- Cited by
- 77
- References
- 85
- Citations by year
- 2023: 1 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 1 · 2014: 1 · 2013: 2 · 2012: 2
- FWCI
- 0.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Immunology and Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Health and Medical Research Council of Australia
- National Multiple Sclerosis Society of Australia
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- activation-induced cell death, immune tolerance, autoreactive T cells, alloreactive T cells, costimulation, target organs, autoimmune disease, allograft acceptance, MHC mismatch, liver transplantation, memory T cells
- MeSH terms
- Animals, Antigen-Presenting Cells, Autoimmune Diseases, Encephalomyelitis, Autoimmune, Experimental, Humans, Immune Tolerance, Lymphocyte Activation, Multiple Sclerosis, T-Lymphocytes, Autoimmunity, Apoptosis, fas Receptor
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