Which Lymphoid Cells Express MHC Class II ; Are TCRs Encoded within the MHC?

This information is current as Ted H. Hansen of October 2, 2021. J Immunol 2011; 187:2043-2044; ; doi: 10.4049/jimmunol.1101982 http://www.jimmunol.org/content/187/5/2043 Downloaded from References This article cites 13 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/187/5/2043.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Which Lymphoid Cells Express MHC Class II Antigens; Are TCRs Encoded within the MHC? Ted H. Hansen

he report by Sachs and Cone (1) is an important nant mouse strains, most of which were generated by the lab- historical paper because it correctly demonstrated oratories of Drs. George Snell, Jack Stimpfling, or Donald T that serologically detected class II MHC Ags are Shreffler. Three different laboratories published papers in expressed on B cells and not T cells. The paper came at an 1973 reporting detection of Ags encoded within the Ir region incredibly exciting time in science, because the products of the MHC. Jan Klein and colleagues (7, 10) reported in encoded within a central region of the mouse MHC had very Science and Journal of Experimental Medicine the characteriza- recently been reported to determine the outcome of different tion of antisera raised by immunizing Ir region-disparate immune functions, namely 1) responses to synthetic peptides mouse strains with lymphoid cells. They designated their Ag Downloaded from and other Ags (2, 3); 2) susceptibility to viruses (4); 3) mixed Ir-1.1 based on their reported detection of Ir-1.1 “only on responses (5); and 4) graft-versus-host reactions -derived T .” In 1973 as well, Shreffler’s (6). Based on the genetic mapping of these immune func- laboratory used a similar approach and reported that their tions, this central region of the mouse MHC was designated antisera to Ags encoded within the Ir region were reactive pre- the Ir, or I, region. Furthermore, because each of these im- dominantly with lymph node cells (11). This group tentatively mune functions was known to involve thymocyte-derived designated their Ag Lna, for lymph node Ag. In striking con- http://www.jimmunol.org/ cells, it was widely speculated that the Ir region encoded trast to these other reports, Sachs and Cone (1) reported in this recognition structures on T cells for Ag, that is, the yet-to- same year that their antisera to gene products encoded within be-defined TCRs. Accordingly, it was speculated by Dr. Jan the Ir region detected B cells and not T cells. They got it right! Klein (7) that the discovery of a new class of T recognition The first approach taken by Sachs and Cone was to raise structures encoded within the MHC would have an enormous heterologous antiserum by immunizing Fischer rats with B10. impact on modern immunology. Conceptually, it was reason- D2 (H-2d) mouse lymphocytes. When tested for reactivity on able in 1973 to speculate that the MHC encoded rec- B10.D2 lymphocytes in complement-mediated cytotoxicity ognition structures, because MHC restriction, determinant se- assays, their heterologous antiserum lysed .80% of the cells, by guest on October 2, 2021 lection, and Ag presentation were all yet to be defined. consistent with its inclusion of Ab to MHC class I molecules. Of note, the partitioning of the MHC into gene products at However, unexpectedly, when they tested their heterologous the time of the Sachs and Cone contribution (1) was based on antiserum on congenic B10 (H-2b) mouse lymphocytes, it comparisons of different mouse strains with genetic crossovers detected cell-surface Ags expressed preferentially on B cells. between MHC-encoded loci as determined typically using se- Thus the cross-reactive Ags expressed by the H-2d and H-2b rological markers. Using this approach, the mouse MHC was MHC haplotypes were not class I Ags, but instead were novel initially subdivided into K, Ir, S, and D regions, such that Ags expressed on B cells. They provisionally called these novel the K and D regions encoded the major transplantation Ags Ags b. Using intra-MHC recombinant mouse strains, they then as detected by allograft rejection or alloantisera, the Ir region mapped determining b expression within or near the Ir encoded the determinants of the aforementioned four immune region. Importantly, Sachs and Cone also reported the detec- T cell functions, and the S region encoded complement com- tion of Ab with anti-b activity in alloantiserum. Their findings ponents (8). Based on a lack of knowledge of the molecular can be explained retrospectively by the fact that I-A proteins basis of these serological and functional assays, it was proposed of the d and b haplotypes are more serologically cross-reactive that genetically mapped loci be classified as either serologically than their respective Kd and Kb class I proteins. In any case, defined or lymphocyte defined (9). Using this obfuscating no- Cone and Sachs correctly determined that Abs to MHC class II menclature, the Ir region in 1973 contained lymphocyte- proteins detect predominantly B cells and not T cells, a finding defined and not serologically defined determinants. To de- corroborated in 1974 by Hammerling et al. (12). It must be termine whether Abs could be generated to Ir region-encoded noted that these observations were made before modern day gene products, several laboratories used intra-MHC recombi- methods of mAb production and identification of specific im- mune cell types by cytometry. Using today’s approaches, it is now clear that MHC class II proteins are highly expressed on Department of Pathology and Immunology, Washington University School of Med- icine, St. Louis, MO 63110 other professional APCs (e.g., dendritic cells and ) Address correspondence and reprint requests to Prof. Ted H. Hansen, Department of in addition to B cells. Furthermore, Ab blocking studies and Pathology and Immunology, Washington University School of Medicine, 660 South genetic approaches have provided unequivocal evidence that Euclid Avenue, St. Louis, MO 63110-1093. E-mail address: [email protected] serologically detected class II molecules on APCs control Ag- 1 Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 specific immune responses of CD4 Tcells. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1101982 2044 PILLARS OF IMMUNOLOGY

In conclusion, the B cell expression of MHC class II dis- 2. McDevitt, H. O., B. D. Deak, D. C. Shreffler, J. Klein, J. H. Stimpfling, and G. D. Snell. 1972. Genetic control of the immune response. Mapping of the covered first by Sachs and Cone (1), in combination with the Ir-1 locus. J. Exp. Med. 135: 1259–1278. elegant genetic mapping studies of the Shreffler, Klein, and 3. Benacerraf, B., and H. O. McDevitt. 1972. Histocompatibility-linked immune response genes. Science 175: 273–279. McDevitt laboratories (7, 10, 11), caused a paradigm shift. 4. Lilly, F. 1968. The effect of histocompatibility-2 type on response to friend leuke- Whereas the bias in 1973 was that the Ir region encoded mia virus in mice. J. Exp. Med. 127: 465–473. TCRs for Ags, the finding of MHC class II expression on 5. Bach, F. H., M. B. Widmer, M. Segall, M. L. Bach, and J. Klein. 1972. Genetic and immunological complexity of major histocompatibility regions. Science 176: 1024– non-T cells laid the foundation for subsequent discoveries 1027. that MHC class II proteins bind peptides for presentation 6. Livnat, S., and J. Klein. 1973. Graft versus host reaction in strains of mice identical 1 for H-2K and H-2D antigens. Nat. New Biol. 243: 42–44. by APCs to CD4 T cells (13). 7. Hauptfeld, V., D. Klein, and J. Klein. 1973. Serological identification of an Ir-region product. Science 181: 167–169. 8. Klein, J., and D. C. Shreffler. 1971. The H-2 model for the major histo- Acknowledgments compatibility systems. Transplant. Rev. 6: 3–29. 9. Bach, F. H., M. B. Widmer, M. L. Bach, and J. Klein. 1972. Serologically defined I thank Drs. Jeff Frelinger, Janet Connolly, Roger Herr, and Xiaoli Wang for and lymphocyte-defined components of the major histocompatibility complex in insightful comments. the mouse. J. Exp. Med. 136: 1430–1444. 10. Go¨tze, D., R. A. Reisfeld, and J. Klein. 1973. Serologic evidence for antigens controlled by the Ir region in mice. J. Exp. Med. 138: 1003–1008. 11. David, C. S., D. C. Shreffler, and J. A. Frelinger. 1973. New lymphocyte Disclosures system (Lna) controlled by the Ir region of the mouse H-2 complex. Proc. Natl. The author has no financial conflicts of interest. Acad. Sci. USA 70: 2509–2514. 12. Hammerling, G. J., B. D. Deak, G. Mauve, U. Hammerling, and H. O. McDevitt. 1974. B-Lymphocyte alloantigens controlled by I-rRegion of mMajor histocompat- ibility complex in mice. Immunogenetics 1: 68–81. Downloaded from References 13. Babbitt, B. P., P. M. Allen, G. Matsueda, E. Haber, and E. R. Unanue. 1985. 1. Sachs, D. H., and J. L. Cone. 1973. A mouse B-cell alloantigen determined by gene(s) Binding of immunogenic peptides to Ia histocompatibility molecules. Nature 317: linked to the major histocompatibility complex. J. Exp. Med. 138: 1289–1304. 359–361. http://www.jimmunol.org/ by guest on October 2, 2021