T cells undergo somatic recombination of the TCR during their development, which provides the possibility to generate an immense diversity of TCRs. It is estimated that a human individual can harbor up to 108 unique TCR sequences. Some of these generated TCRs recognize the same antigen and form antigen-specific precursor populations of naïve T cells. The size of antigen-specific precursor populations depends on the epitope and is estimated to harbor between 1 and 104 different clonotypes with a diverse avidity distribution. Antigen-specific adaptive immune responses arise from these polyclonal repertoires of naïve precursors. Upon antigen encounter, individual T-cell clones are recruited into the immune response, clonally expand and differentiate into memory and effector subsets. During this process, T cells with a high affinity TCR are preferentially selected during the acute phase of the immune response. However, depending on the disease context, epitope and type of immune response different TCR repertoires of different diversities are maintained over the course of clonal selection and time. TCR recruitment is governed by clear avidity thresholds, including a large number of low-avidity T-cell clones in primary immune responses. Although the immune response is quickly dominated by high-avidity T-cell clones, low-avidity T cells are still capable of forming small memory populations, providing a flexible niche for secondary immune responses. These memory populations can play a crucial role in protection against mutational escape variants, as commonly encountered in infectious disease. We seek to understand the role of low-avidity T cells and polyclonality in immune responses more clearly in order to improve vaccination strategies and cellular therapies.
