Antigen affinity and antigen dose exert distinct influences on CD4 T-cell differentiation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-10, Vol.111 (41), p.14852-14857
• Main Authors: Keck, Simone, Schmaler, Mathias, Ganter, Stefan, Wyss, Lena, Oberle, Susanne, Huseby, Eric S., Zehn, Dietmar, King, Carolyn G.
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Antigens - immunology; B lymphocytes; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Biological Sciences; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; Cell Differentiation - immunology; Cell Proliferation; Dosage; Dose-Response Relationship, Immunologic; Immunity; Immunologic Memory; Infections; Interleukin-2 - metabolism; Ligands; Lymphocyte Activation - immunology; Major Histocompatibility Complex; Memory; Mice; Receptors; Receptors, Antigen, T-Cell - immunology; Signal transduction; T cell antigen receptors; T cell receptors; T lymphocytes; Th1 Cells - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1403271111

Significance T-cell receptor recognition of antigen is an essential first step in the initiation of a T-cell response. This report demonstrates that CD4 T cells responding during an infection can discriminate between antigen affinity and antigen dose, resulting in distinct types of effector and memory cell generation. Moreover, memory T cells “remember” the strength of primary T-cell activation and maintain a biased recall response upon secondary infection. These data reveal that antigen affinity exerts an important influence on T-cell differentiation that is not compensated for by high antigen dose. Understanding the rules of CD4 T-cell differentiation is integral to effective vaccine design. Cumulative T-cell receptor signal strength and ensuing T-cell responses are affected by both antigen affinity and antigen dose. Here we examined the distinct contributions of these parameters to CD4 T-cell differentiation during infection. We found that high antigen affinity positively correlates with T helper (Th)1 differentiation at both high and low doses of antigen. In contrast, follicular helper T cell (T FH) effectors are generated after priming with high, intermediate, and low affinity ligand. Unexpectedly, memory T cells generated after priming with very low affinity antigen remain impaired in their ability to generate secondary Th1 effectors, despite being recalled with high affinity antigen. These data challenge the view that only strongly stimulated CD4 T cells are capable of differentiating into the T FH and memory T-cell compartments and reveal that differential strength of stimulation during primary T-cell activation imprints unique and long lasting T-cell differentiation programs.