Single‐cell fate mapping reveals widespread clonal ignorance of low‐affinity T cells exposed to systemic infection

• Published in: European journal of immunology 2023-03, Vol.53 (3), p.e2250009-n/a
• Main Authors: Leube, Justin, Mühlbauer, Anton, Andrä, Immanuel, Biggel, Madleen, Busch, Dirk H., Kretschmer, Lorenz, Buchholz, Veit R.
• Format: Article
• Language: English
• Subjects: Affinity; Antigens; Autoantigens; CD8 antigen; CD8-Positive T-Lymphocytes; Cell Differentiation; Cell fate; Disseminated infection; Fate maps; Flow cytometry; Immune Tolerance; Immunization; Immunological tolerance; Infections; Inflammation; Lymphocytes; Lymphocytes T; single‐cell fate mapping; Systemic diseases; T cell ignorance; T cell receptor affinity; T cell recruitment; T cell tolerance
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.202250009

T cell ignorance is a specific form of immunological tolerance. It describes the maintenance of naivety in antigen‐specific T cells in vivo despite the presence of their target antigen. It is thought to mainly play a role during the steady state, when self‐antigens are presented in absence of costimulatory signals and at low density or to T cells of low affinity. In how far antigen‐specific T cells can also remain clonally ignorant to foreign antigens, presented in the inflammatory context of systemic infection, remains unclear. Using single‐cell in vivo fate mapping and high throughput flow cytometric enrichment, we find that high‐affinity antigen‐specific CD8+ T cells are efficiently recruited upon systemic infection. In contrast, most low‐affinity antigen‐specific T cells ignore the priming antigen and persist in the naïve state while remaining fully responsive to subsequent immunization with a high‐affinity ligand. These data establish the widespread clonal ignorance of low‐affinity T cells as a major factor shaping the composition of antigen‐specific CD8+ T cell responses to systemic infection. Clonal ignorance describes the maintenance of T cell naivety despite the presence of cognate antigen in vivo. Generally this tolerance mechanism is thought to play a role only during the steady state. Instead, single‐cell fate mapping reveals that upon low‐affinity T cell receptor stimulation, the bulk of antigen‐specific CD8+ T cells remain ignorant, even in the context of systemic infection.