TCR repertoire evolution during maintenance of CMV‐specific T‐cell populations

Abstract

During infections and cancer, the composition of the T-cell receptor (TCR) repertoire of antigen-specific CD8 T cells changes over time. TCR avidity is thought to be a major driver of this process, thereby interacting with several additional regulators of T-cell responses to form a composite immune response architecture. Infections with latent viruses, such as cytomegalovirus (CMV), can lead to large T-cell responses characterized by an oligoclonal TCR repertoire. Here, we review the current status of experimental studies and theoretical models of TCR repertoire evolution during CMV infection. We will particularly discuss the degree to which this process may be determined through structural TCR avidity. As engineered TCR-redirected T cells have moved into the spotlight for providing more effective immunotherapies, it is essential to understand how the key features of a given TCR influence T-cell expansion and maintenance in settings of infection or malignancy. Deeper insights into these mechanisms will improve our basic understanding of T-cell immunology and help to identify optimal TCRs for immunotherapy.

Dimensions of immunologic memory

“…Yet another organizing principle for the presentation of the articles in this volume is the preferred temporospatial context explored for immunological memories. An emphasis on anatomic niches such as primary and secondary lymphoid organs, non‐lymphoid tissues including tumors is accompanied by temporal considerations that range from details of T‐ and B‐cell memory generation and maintenance to evolution at large . Altogether, we agree with the conclusion proposed in the introductory review; that immunologic memory is best conceived of as a multi‐dimensional concept with physical correlates in far more components of the adaptive and innate immune system than previously appreciated.…”

“…This is perhaps best illustrated by the prominence of “memory inflation,” the numerical expansion of virus‐specific memory T cells in certain experimental and naturally occurring scenarios as emphasized by several contributors . At the same time, the very concept of “immunological memory” has undergone a substantial “inflation” (as it were) of its own, being now invoked for cell types other than T and B cells (innate lymphocytes, monocyte/macrophages) and species other than vertebrates (invertebrates, plants, archaea, and bacteria) .…”

“…At the same time, the very concept of “immunological memory” has undergone a substantial “inflation” (as it were) of its own, being now invoked for cell types other than T and B cells (innate lymphocytes, monocyte/macrophages) and species other than vertebrates (invertebrates, plants, archaea, and bacteria) . Another topic extensively discussed throughout this issue is the role of persisting antigen in shaping immunological memory in the context of chronic viral infections, cancer and the preservation of protective immunity . This perspective in turn is complemented by reviews that outline the particular role of antigen receptors and other facets such as cytokines and fat metabolism in control of memory generation and maintenance .…”

“…This perspective in turn is complemented by reviews that outline the particular role of antigen receptors and other facets such as cytokines and fat metabolism in control of memory generation and maintenance . Perhaps not surprisingly, the diverse dimensions of immunological memory are expounded by more reviews for CD8 + T cells than those devoted to additional T‐cell subsets or B cells . We assume this to be more the result of the collective research attention (what one might call “herd immunology”) than the importance of any one cell type in immunological memory and host protection.…”

Immunological Diversity with Similarity

“…Diversity both affects function and reflects it. In the adaptive immune system, the defining 300 tradeoff is breadth vs. depth: a repertoire must be sufficiently diverse to contain sequences that 301 can recognize a given target and lead to useful clones, but not so diverse that cells that express 302 such sequences are too rare to encounter their target on biologically meaningful timescales 30,31 . 303…”