Shaping the T Cell Repertoire

Shaping the T Cell Repertoire Harald von Boehmer J Immunol 2005; 175:7067-7068; ; This information is current as doi: 10.4049/jimmunol.175.11.7067 of September 27, 2021. http://www.jimmunol.org/content/175/11/7067 Downloaded from References This article cites 6 articles, 3 of which you can access for free at: http://www.jimmunol.org/content/175/11/7067.full#ref-list-1

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Today immunologists are well aware of positive to self. In this hypothesis, the focus on self-MHC was imposed and negative selection of developing T cells. This by MHC molecules as expressed on radioresistant tissue only as was very different almost three decades ago when opposed to MHC molecules that were expressed on hemopoi- MHC-restricted Ag recognition by T cells repre- etic cells. sented an enormous puzzle in the absence of data on the mo- Even though the experiments did not directly address that lecular nature of Ag recognition by T cells. It was at this time point, Bevan assumed that the repertoire bias was due to intra- that Bevan (1) published a report that provided a first hint for thymic selection of cells before rather than after immunization. positive selection of lymphocytes. Although Bevan was first to publish data consistent with T cell In 1971, the Danish immunologist Niels Kai Jerne had pro- repertoire selection by MHC molecules, it was his colleague Downloaded from posed a bold theory designed to explain the high frequency of T Rolf Zinkernagel who, by letting MHC ab heterozygous bone cells specific for allogeneic MHC molecules and MHC-linked marrow cells develop in MHC homozygous aa or bb thymus immune response genes. He assumed that germline-encoded grafts before immunization, separated intrathymic repertoire TCRs were specific for MHC Ags of the species and that spec- selection from repertoire selection due to immunization in pe- ificity for non-MHC Ags arose by somatic mutation of TCR ripheral lymphoid tissue. Thus, these experiments convincingly http://www.jimmunol.org/ genes in cells selected and stimulated by self-MHC molecules to showed that the thymus influenced the T cell repertoire before proliferate in the thymus (2). At the time, Jerne did not know deliberate immunization (3). about MHC-restricted Ag recognition by T cells. Jerne’s ideas The experiments by both Bevan and Zinkernagel had an im- were nevertheless popular with some investigators who dealt mense impact on the scientific community in that T cell reper- with the notion of MHC-restricted Ag recognition by T cells toire selection by thymic MHC molecules became a hotly de- and postulated selection of cells in the thymus according to bated and very controversial issue, even more so because the their TCR specificity as a mechanism to focus the T cell reper- nature of the TCR was obscure at the time and the proposed toire onto recognition of self MHC. It was Bevan (1) who re- selection by MHC molecules suggested to some investigators ported the first experiment that was consistent with such ideas. by guest on September 27, 2021 that MHC molecules and non-MHC Ags could be recognized Previous experiments in chimeric mice generated by injecting T as distinct entities. This was evident from the title of Zinkerna- cell-depleted MHC homozygous aa bone marrow cells into gel’s article “On the thymus in the differentiation of ‘H-2 self- MHC heterozygous ab x-irradiated recipients had shown that recognition’ by T cells: evidence for dual recognition?” (2). in this scenario the newly formed aa T cells were tolerant of b However, since the bias in terms of MHC restriction was often MHC molecules. After appropriate immunization, aa T cells not found to be absolute (there were MHC b-restricted cells specific for non-MHC Ags presented by either a or b MHC that had matured in a MHC homozygous aa thymus), the term molecules occurred in roughly equal frequency. Bevan reversed this setup by injecting MHC heterozygous ab bone marrow “bending” of the T cell repertoire was invented, which perhaps cells into x-irradiated MHC homozygous aa recipients and was most appropriate for the original models proposed by Jerne noted that after immunization and in vitro restimulation with (2), Bevan (1), and Zinkernagel (3), who all invoked expansion minor histocompatibility Ags, the thus-generated cytolytic T of certain cells selected by thymic MHC molecules but not cells lysed preferentially targets that presented these minor H other cells as a mechanism to shape the T cell repertoire. Ags in the context of a but not b MHC molecules. Importantly, At the time, Ag processing, peptide MHC-complexes and the he also showed that the bias was turned around when the bone nature of the TCR were not yet known. Therefore, it may not marrow cells were injected into an MHC homozygous bb be surprising that it would take another decade to discover that mouse, i.e., now T cells were mostly restricted by b MHC mol- the models of Jerne, Bevan, and Zinkernagel were in fact wrong ecules. To explain these results, Bevan adopted and revised in that all and not only a subset of immature T cells underwent Jerne’s idea of T cell repertoire shaping by postulating that T positive selection, i.e., positive selection was required for the cells recognized MHC molecules “altered” by other surface generation of all mature T cells. Thus, even T cells specific for molecules (altered self). He further proposed that T cells se- allogeneic MHC Ags need to be positively selected by “self” lected by self-MHC molecules in the thymus would proliferate MHC molecules. Furthermore, the mechanism of positive se- and mutate their receptors such that they would preferentially lection involved selective survival and maturation among mor- recognize “altered-self” MHC molecules, which were “similar” ibund thymocytes rather than expansion of a selected subset. Finally, somatic mutation in Jerne’s sense played no role in the generation of the T cell repertoire. Most importantly, it became 1 Address correspondence and reprint requests to Dr. Harald von Boehmer, Harvard Med- ical School, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. E-mail evident that positive selection served the purpose to align the address: [email protected] specificity of the TCR for class I and II MHC molecules with

Ϫ ϩ ϩ Ϫ the CD4 8 cytolytic and CD4 8 helper phenotype of In this context, the pioneering studies of Michael J. Bevan TCR-expressing cells, respectively (reviewed in Ref. 4). This have to be viewed as catalytic in that their design and interpre- alignment is responsible for the well-known fact that cells pre- tation represented a first step in the right direction at a time senting cytosolic peptides by class I MHC molecules (virus-in- when little was known about the molecular nature of MHC- ϩ fected cells) are destroyed by cytolytic CD8 T cells, whereas restricted Ag recognition by T cells. cells presenting peptides generated in the endocytic pathway by class II molecules (Ag-presenting B cells) induce the production ϩ of cytokines in responding CD4 T cells. The differentiation of References functionally distinct subsets of T cells with expression of differ- 1. Bevan, M. J. 1975. The major histocompatibility complex determines susceptibility to cytotoxic T cells directed against minor histocompatibility antigens. J. Exp. Med. 142: ent surface markers was initially described by Cantor and Boyse 1349–1364. (5), as well as Kisielow et al. (6), before the notion of positive 2. Jerne, N. K. 1971. The somatic generation of immune recognition. Eur. J. Immunol. selection and raised important questions with regard to the 1: 1–9. 3. Zinkernagel, R. M., G. N. Callahan, A. Althage, S. Cooper, P. A. Klein, and J. Klein. alignment of specificity and function of T cell subsets. 1978. On the thymus in the differentiation of “H-2 self-recognition” by T cells: evi- Likewise, it took a decade to discover that the T cell rep- dence for dual recognition? J. Exp. Med. 147: 882–896. ertoire was not only shaped by positive but also by negative 4. von Boehmer, H. 2004. Selection of the T cell repertoire: receptor-controlled check- selection, i.e., elimination of potentially harmful cells. Fur- points in T cell development. Adv. Immunol. 84: 201–238. 5. Cantor, H., and E. A. Boyse. 1975. Functional subclasses of T lymphocytes bearing thermore, more recent studies have established TCR-medi- different Ly antigens. I. The generation of functionally distinct T cell subclasses is a ated positive selection as a general mechanism of T lineage differentiative process independent of antigen. J. Exp. Med. 141: 1376–1389. Downloaded from 6. Kisielow, P., J. A. Hirst, H. Shiku, P. C. Beverley, M. K. Hoffman, E. A. Boyse, and fate determination, including that of NK T and suppressor T H. F. Oettgen. 1975. Ly antigens as markers for functionally distinct subpopulations cells (reviewed in Ref. 4). of thymus-derived lymphocytes of the mouse. Nature 253: 219–220. http://www.jimmunol.org/ by guest on September 27, 2021 The Journal of Immunology

CORRECTIONS

Bevan, M. J. 2005. Pillars article: the major histocompatibility complex determines susceptibility to cytotoxic T cells directed against minor histocompatibility antigens. J. Exp. Med 1975. 142: 1349–1364. J. Immunol. 175: 7069–7084.

The article listed above accompanied the December 1, 2005 Pillars of Immunology commentary (von Boehmer, H. 2005. Shaping the T cell repertoire. J. Immunol. 175: 7067–7068) in error. The commentary and correct Pillars Article are published in the present issue of The Journal of Immunology: Bevan, M. J. 2006. Pillars article: in a radiaiton chimaera, host H-2 antigens determine immune responsiveness of donor cytotoxic cells. 1977. Nature 269: 417–418. J. Immunol. 176: 7067–7068.

von Boehmer, H. 2005. Shaping the T cell repertoire. J. Immunol. 175: 7067–7068.

Reference 1 was incorrectly cited. The corrected reference is shown below.

1. Bevan, M. J. 1977. In a radiation chimaera, host H-2 antigens determine immune responsiveness of donor cytotoxic cells. Nature 269: 417–418.

CORRECTIONS

von Boehmer, H. 2005. Shaping the T cell repertoire. J. Immunol. 175: 7067–7068.

Reference 1 was incorrectly cited. The corrected reference is shown below.

1. Bevan, M. J. 1977. In a radiation chimaera, host H-2 antigens determine immune responsiveness of donor cytotoxic cells. Nature 269: 417–418.