Gene complementation in the T-lymphocyte proliferative response to poly (Glu55Lys36Phe9)n. A demonstration that both immune response gene products must be expressed in the same antigen-presenting cell

The immune response (Ir) to the random copolymer GLphi depends upon the function of two Ir genes, Ir-GLphi-beta[beta] and Ir-GLphi- alpha[alpha], mapped to the I-A and I-E/C subregions of the major histocompatibility complex, respectively. In this paper, the site(s) of expression of the products of these two Ir genes was examined by evaluating T-lymphocyte proliferative responses of bone marrow radiation chimeras. Chimeras were created in [alpha+beta- X alpha- beta+]F1 responder mice by lethal irradiation and reconstitution with a mixture of bone marrow cells from both parental strains. These chimeras failed to respond to GLphi, although they were capable or responding to the much weaker antigens, (T,G)-A--L, TEPC-15, pigeon cytochrome c, and (H,G)-A--L. This failure to respond to GLphi was shown not to be the result of a cryptic mixed lymphocyte reaction, as similar chimeras created in (alpha+beta+ X alpha-beta+)F1 mice responded well to GLphi, although they possessed almost the same potential histoincompatibility. Furthermore, the lack of response to GLphi could not be attributed to a general failure of the two parental cell types in the chimeras to collaboratc with each other, as each chimeric parental cell type could respond to dinitrophenyl conjugated ovalbumin presented on nonimmune spleen cells from the other parent. Thus, the failure of low responder parental into F1 high responder chimeras to generate an immune response to GLphi suggests that immune competence for this antigen requires at least one cell type in the immune system to express gene products of both the Ir-glphi-alpha and -beta genes, i.e. one cell must be of high responder genotype. The the antigen-presenting cell is one such cell type was shown by experiments in which GLphi-primed T lymphocytes from responder F1 mice were stimulated with antigen bound to nonimmune spleen cells. Only spleen cells from responder F1 and recombinant mice could present GLphi. Neither of the two complementing nonresponder parental spleen cell populations, either alone or mixed together, could present GLphi, although both could present purified protein derivative of tuberculin. This was shown to be the case for T cells positively selected in vitro as well as freshly explanted T cells. Thus, both Ir- GLphi-alpha and Ir-GLphi-beta gene products must be expressed in the same antigen-presenting cell to generate a T-lymphocyte proliferative response to GLphi. The implications of these findings for models of two gene complementation are discussed.

[1]  T. M. Dexter Natural Resistance Systems against Foreign Cells, Tumors and Microbes , 1979, British Journal of Cancer.

[2]  H. Mcdevitt,et al.  Two-gene control of the expression of a murine Ia antigen , 1978, The Journal of experimental medicine.

[3]  E. Margoliash,et al.  Genetic control of the T-lymphocyte proliferative response to cytochrome c. , 1978, Advances in experimental medicine and biology.

[4]  W. Paul,et al.  Interaction Between Antigen‐Presenting Cells and Primed T Lymphocytes , 1978, Immunological reviews.

[5]  A. Rosenthal Determinant Selection and Macrophage Function in Genetic Control of the Immune Response , 1978, Immunological reviews.

[6]  L. Rosenwasser,et al.  Adherent cell function in murine T lymphocyte antigen recognition. I. A. macrophage-dependent T cell proliferation assay in the mouse. , 1978, Journal of immunology.

[7]  W. Paul,et al.  Inhibition of dual Ir gene-controlled T-lymphocyte proliferative response to poly (Glu56Lys35Phe9)n with anti-Ia antisera directed against products of either I-A or I-C subregion. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[8]  A. Schechter,et al.  Genetic control of the T lymphocyte proliferative response to staphylococcal nuclease: evidence for multiple MHC-linked Ir gene control. , 1978, Journal of immunology.

[9]  W. Paul,et al.  Antigen presentation in the murine T lymphocyte proliferative response. II. Ir‐GAT‐controlled T lymphocyte responses require antigen‐presenting cells from a high responder donor , 1978, European journal of immunology.

[10]  N. K. Jerne,et al.  Major histocompatibility complex-linked immune-responsiveness is acquired by lymphocytes of low-responder mice differentiating in thymus of high-responder mice. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[11]  R. Zinkernagel,et al.  On the thymus in the differentiation of "H-2 self-recognition" by T cells: evidence for dual recognition? , 1978, The Journal of experimental medicine.

[12]  J. Klein,et al.  The lymphoreticular system in triggering virus plus self-specific cytotoxic T cells: evidence for T help , 1978, The Journal of experimental medicine.

[13]  R. Schwartz A Clonal Deletion Model for Ir Gene Control of the Immune Response , 1978, Scandinavian journal of immunology.

[14]  K. Okuda,et al.  The role of gene products of the I-J subregion in mixed lymphocyte reactions , 1977, The Journal of experimental medicine.

[15]  R. Gorczynski,et al.  Differentiation of functionally active mouse T-lymphocytes from functionally inactive bone marrow precursors. , 1977, Immunology.

[16]  K. Keck Ir gene control of carrier recognition III.cooperative recognition of two or more carrier determinants on insulins of different lspecies , 1977, European journal of immunology.

[17]  M. Bevan In a radiation chimaera, host H–2 antigens determine immune responsiveness of donor cytotoxic cells , 1977, Nature.

[18]  R. Schwartz,et al.  Antigen presentation in the murine T-lymphocyte proliferative response. I. Requirement for genetic identity at the major histocompatibility complex , 1977, The Journal of experimental medicine.

[19]  H. Etlinger,et al.  Lymphocyte specificity to protein antigens. I. Characterization of the antigen-induced in vitro T cell-dependent proliferative response with lymph node cells from primed mice. , 1977, Journal of immunology.

[20]  E. Shevach,et al.  The Role of Ia Antigens in T Cell Activation , 1977, Immunological reviews.

[21]  W. Paul,et al.  Functional specificity of thymus- dependent lymphocytes , 1977, Science.

[22]  C. Warner,et al.  The immune response of allophenic mice to the synthetic polymer L-glutamic acid, L-lysine, L-phenylalanine. II. Lack of gene complementation in two nonresponder strains , 1977, The Journal of experimental medicine.

[23]  W. Paul,et al.  T-lymphocyte-enriched murine peritoneal exudate cells. IV. Genetic control of cross-stimulation at the T-cell level , 1977, Journal of Experimental Medicine.

[24]  C. Janeway,et al.  Two Different VH Gene Products Make Up the T‐Cell Receptors , 1976, Scandinavian journal of immunology.

[25]  J. Gamble,et al.  Role of major histocompatibility complex gene products in delayed-type hypersensitivity. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[26]  W. Paul,et al.  The requirement for two complementing Ir-GLphi immune response genes in the T-lymphocyte proliferative response to poly-(Glu53Lys36Phe11) , 1976, The Journal of experimental medicine.

[27]  W. Paul,et al.  T-lymphocyte-enriched murine peritoneal exudate cells. II. Genetic control of antigen-induced T-lymphocyte proliferation , 1976, The Journal of experimental medicine.

[28]  W. Paul,et al.  T lymphocyte-enriched murine peritoneal exudate cells. I. A reliable assay for antigen-induced T lymphocyte proliferation. , 1975, Journal of immunology.

[29]  E. Rüde,et al.  Genetic complementation of histocompatibility-linked Ir genes in the rat. , 1975, Journal of immunology.

[30]  J. Sprent,et al.  Collaboration of histoincompatible T and B lymphocytes using cells from tetraparental bone marrow chimeras , 1975, The Journal of experimental medicine.

[31]  B. Benacerraf,et al.  Complementation of H-2-linked Ir genes in the mouse. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J. Sprent,et al.  Association of immunity and tolerance to host H-2 determinants in irradiated F1 hybrid mice reconstituted with bone marrow cells from one parental strain , 1975, The Journal of experimental medicine.

[33]  M. Taussig,et al.  Two genes in the major histocompatibility complex control immune response , 1975, Nature.

[34]  B. Benacerraf,et al.  Requirement for two H-2 complex Ir genes for the immune response to the L-glu, L-lys,L-phe terpolymer. , 1975, The Journal of experimental medicine.

[35]  J. Sprent,et al.  Tolerance to histocompatibility determinants in tetraparental bone marrow chimeras , 1975, The Journal of experimental medicine.

[36]  J. Frelinger,et al.  New lymphocyte antigen system (Lna) controlled by the Ir region of the mouse H-2 complex. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[37]  J. Waldron,et al.  Antigen-induced proliferation of guinea pig lymphocytes in vitro: obligatory role of macrophages in the recognition of antigen by immune T-lymphocytes. , 1973, Journal of immunology.

[38]  T. Meo,et al.  A major role for the Ir-1 region of the mouse H-2 complex in the mixed leukocyte reaction. , 1973, Transplantation proceedings.

[39]  B. Chesebro,et al.  Affinity labeling of a phosphorylcholine binding mouse myeloma protein. , 1972, Biochemistry.

[40]  M. Sela,et al.  Studies on the chemical basis of the antigenicity of proteins. 5. Synthesis, characterization and immunogenicity of some multichain and linear polypeptides containing tyrosine. , 1962, The Biochemical journal.

[41]  E. Margoliash,et al.  Mitochondrial cytochrome c: preparation and activity of native and chemically modified cytochromes c. , 1978, Methods in enzymology.

[42]  W. Paul,et al.  Gene complementation in the T-lymphocyte proliferative response to poly (Glu55Lys36Phe9)n. A demonstration that both immune response gene products must be expressed in the same antigen-presenting cell , 1979, The Journal of experimental medicine.

[43]  K. Rajewsky,et al.  FUNCTIONAL COMPLEMENTATION AND POLYMORPHISM OF H-2 LINKED IMMUNE RESPONSE GENES , 1978 .

[44]  O. Stutman THYMIC FUNCTIONS AND RESISTANCE TO FOREIGN HEMOPOIETIC GRAFTS , 1978 .