TIRC7 inhibits T cell proliferation by modulation of CTLA-4 expression.
Ab targeting of TIRC7 has been shown previously to inhibit T cell proliferation and Th1 lymphocyte-associated cytokine production. In this study, we demonstrate that Ab targeting of TIRC7 induces early cell surface expression of CTLA-4. The majority of stimulated CD4+ and CD8+ human T cells coexpress CTLA-4 and TIRC7. Similar to CTLA-4, TIRC7 rapidly accumulates at the site of Ag adhesion upon T cell activation. TIRC7 seems to colocalize with CTLA-4 in human T cells, and both molecules are associated with clathrin-coated vesicles, indicating they share intracellular transport systems. Moreover, Ab targeting of TIRC7 results in an early activation of CTLA-4 transcription. The inhibition of cell proliferation mediated by TIRC7 is dependent on CTLA-4 expression because the TIRC7-mediated inhibitory effects on cell proliferation and cytokine expression are abolished by Ab blockade of CTLA-4. Splenocytes obtained from CTLA-4-deficient mice are not responsive to TIRC7 Ab targeting. Thus, TIRC7 acts as an upstream regulatory molecule of CTLA-4 expression.
Bulwin
Grit-Carsta
GC
Institut für Medizinische Immunologie, Campus Charité Mitte, Humboldt-Universität zu Berlin, Berlin, Germany.
Heinemann
Thomas
T
Bugge
Volker
V
Winter
Michael
M
Lohan
Anke
A
Schlawinsky
Mirko
M
Schulze
Anke
A
Wälter
Stephanie
S
Sabat
Robert
R
Schülein
Ralf
R
Wiesner
Burkhard
B
Veh
Rüdiger W
RW
Löhler
Jürgen
J
Blumberg
Richard S
RS
Volk
Hans-Dieter
HD
Utku
Nalân
N
D019138:Antibodies, Blocking / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000096:biosynthesis* / Q000276:immunology / Q000502:physiology; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000276:immunology / Q000502:physiology; D001665:Binding Sites / Q000276:immunology; D060908:CTLA-4 Antigen; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D022163:Clathrin-Coated Vesicles / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D021381:Protein Transport / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology; D025262:Vacuolar Proton-Translocating ATPases / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D016207:Cytokines; D006131:Growth Inhibitors; D007106:Immune Sera; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; C472421:TCIRG1 protein, human; D025262:Vacuolar Proton-Translocating ATPases