A rheostatic mechanism for T-cell inhibition based on elevation of activation thresholds.
The activation of discrete T-cell responses depends on the triggering of individualized threshold numbers of T-cell receptors (TCRs). The results of this study indicate that the lipocalin placental protein 14 (PP14), a T-cell inhibitor produced by cells of the reproductive and hematopoietic systems, mediates its anti-inflammatory activity by elevating the T-cell activation threshold, thereby rendering T cells less sensitive to stimulation. Significantly, the data demonstrate hierarchical sensitivity of selected cytokine responses to PP14-mediated inhibition, with the hierarchy reflecting their respective activation thresholds. These findings suggest a novel paradigm for immunoinhibition wherein negative regulators can finely tune, rather than inactivate, T-cell responses, and thereby skew the cytokine output of immunologic responses.
Rachmilewitz
J
J
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Riely
G J
GJ
Huang
J H
JH
Chen
A
A
Tykocinski
M L
ML
D000653:Amniotic Fluid / Q000502:physiology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D016466:CHO Cells / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D000071816:Glycodelin; D006023:Glycoproteins / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007142:Immunoglobulin gamma-Chains / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D010835:Phytohemagglutinins / Q000494:pharmacology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011993:Recombinant Fusion Proteins; D012212:Rheology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014162:Transfection
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D000071816:Glycodelin; D006023:Glycoproteins; D007141:Immunoglobulin Fc Fragments; D007142:Immunoglobulin gamma-Chains; D007166:Immunosuppressive Agents; D007376:Interleukin-2; C045246:PAEP protein, human; D010835:Phytohemagglutinins; D011257:Pregnancy Proteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma