Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Sep 17;383(12):1156-1166.
doi: 10.1056/NEJMra1911109.

Tolerance in the Age of Immunotherapy

Jeffrey A Bluestone  1 , Mark Anderson  1
Affiliations
Review

Tolerance in the Age of Immunotherapy

Jeffrey A Bluestone et al. N Engl J Med. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Figures

Figure 1.
Figure 1.. Two-Signal Models of Costimulatory and Inhibitory Pathways.
Initiation of a productive T-cell response involves integration of a primary signal delivered through the T-cell receptor (TCR) and major histocompatibility complex (MHC)–peptide, followed by a second signal delivered through the CD28–CD80 or CD28–CD86 pathway (Panel A). After initiation of T-cell activation, other inhibitory checkpoint interactions can shut down T-cell activity (Panel B). Pathways that may be affected as a consequence of both positive and negative second signals are listed at the bottom of the figure. CTLA-4 denotes cytotoxic T-lymphocyte–associated protein 4.
Figure 2.
Figure 2.. Additional Costimulatory and Checkpoint Pathways.
In addition to the two-signal models of costimulatory and checkpoint pathways, additional stimulatory and inhibitory pathways (indicated by plus and minus signs, respectively) influence the immune response, including molecules of the tumor necrosis factor (TNF)–related family, other members of the CD28 family, adhesion molecules, and T-cell immunoglobulin and mucin (TIM) molecules. The various stimulatory and inhibitory pathways can influence and be influenced by cytokines. Pep denotes peptide, and TGF-β transforming growth factor β.
Figure 3.
Figure 3.. Tolerance-Inducing Pathways in the Thymus and Periphery.
The majority of cells interacting with autoimmune regulator (AIRE)–expressing medullary thymic epithelial cells (mTECs) during thymic development undergo negative selection and die (Panel A). A subset of high-affinity, self-reactive CD4+ T cells interact with the mTECs, leading to the development of regulatory T cells (Tregs). The remaining mature naive T cells migrate into the immune periphery, where they have either a pathogenic role in mediating immunity (Panel B, left) or a protective role as peripherally derived Tregs (through interaction with tolerogenic antigen-presenting cells and cytokines) that control potential autoreactive responses (Panel B, right). Additional cell types, such as extrathymic AIRE–expressing cells (eTACs), can also modify potentially autoreactive T cells.
Figure 4.
Figure 4.. Activation and Functional Consequences of Suppressive Cells.
Tregs and other suppressive cells circulate and reside in lymphoid and somatic tissues to control unwanted autoimmune and inflammatory responses. Multiple cell–cell contacts, as well as soluble molecules (including the roduction of metabolites by microbiota), are generated by Tregs or antigen-presenting cells after Treg interactions to control immunity. Tregs can also act through bystander suppression, leading to dominant local immunosuppression and tolerance induction. IDO denotes indoleamine 2,3-dioxygenase, SCFA short-chain fatty acid, Th3 type 3 helper T cell, and Tr1 type 1 regulatory T cell.
See this image and copyright information in PMC

References

    1. Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature 1953; 172: 603–6. - PubMed
    1. Cooper MD, Peterson RD, Good RA. Delineation of the thymic and bursal lymphoid systems in the chicken. Nature 1965; 205: 143–6. - PubMed
    1. Miller JFAP. The golden anniversary of the thymus. Nat Rev Immunol 2011; 11: 489–95. - PubMed
    1. Klein L, Kyewski B, Allen PM, Hogquist KA. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat Rev Immunol 2014; 14: 377–91. - PMC - PubMed
    1. van Meerwijk JPM, Marguerat S, Lees RK, Germain RN, Fowlkes BJ, MacDonald HR. Quantitative impact of thymic clonal deletion on the T cell repertoire. J Exp Med 1997; 185: 377–83. - PMC - PubMed