Transgenic expression of Ly49A on T cells impairs a specific antitumor response.
Inhibitory MHC receptors determine the reactivity and specificity of NK cells. These receptors can also regulate T cells by modulating TCR-induced effector functions such as cytotoxicity, cytokine production, and proliferation. Here we have assessed the capacity of mouse T cells expressing the inhibitory MHC class I receptor Ly49A to respond to a well-defined tumor Ag in vivo using Ly49A transgenic mice. We find that the presence of Ly49A on the vast majority of lymphocytes prevents the development of a significant Ag-specific CD8+ T cell response and, consequently, the rejection of the tumor. Despite minor alterations in the TCR repertoire of CD8+ T cells in the transgenic lines, precursors of functional tumor-specific CD8+ T cells exist but could not be activated most likely due to a lack of appropriate CD4+ T cell help. Surprisingly, all of these effects are observed in the absence of a known ligand for the Ly49A receptor as defined by its ability to regulate NK cell function. Indeed, we found that the above effects on T cells may be based on a weak interaction of Ly49A with Kb or Db class I molecules. Thus, our data demonstrate that enforced expression of a Ly49A receptor on conventional T cells prevents a specific immune response in vivo and suggest that the functions of T and NK cells are differentially sensitive to the presence of inhibitory MHC class I receptors.
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland.
P
P
Brawand
F A
FA
Lemonnier
H R
HR
MacDonald
J C
JC
Cerottini
W
W
Held
D000818:Animals; D000950:Antigens, Ly; D000956:Antigens, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006183:H-2 Antigens / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D; D016056:Immunodominant Epitopes / Q000276:immunology; D037181:Lectins, C-Type; D007942:Leukemia, Experimental / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D008213:Lymphocyte Activation / Q000235:genetics; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008979:Moloney murine leukemia virus / Q000276:immunology; D055650:NK Cell Lectin-Like Receptor Subfamily A; D009368:Neoplasm Transplantation; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics*; D055630:Receptors, NK Cell Lectin-Like; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D019076:Transgenes / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000637:transplantation
D000950:Antigens, Ly; D000956:Antigens, Viral; D002352:Carrier Proteins; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D016056:Immunodominant Epitopes; C527088:Klra1 protein, mouse; D037181:Lectins, C-Type; D008565:Membrane Proteins; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like