Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor.
Immune responses can be enhanced or dampened by differential manipulation of Foxp3-expressing CD25(+)CD4(+) natural regulatory T (Treg) cells versus other naive or activated T cells. By searching for a molecule capable of distinguishing these populations, we here found that natural Treg cells constitutively expressed high amounts of folate receptor 4 (FR4). The expression of FR4 and CD25 also separated antigen-stimulated CD4(+) non-Treg cells into the FR4(hi)CD25(-) and FR4(lo)CD25(+) populations, which were different in proliferation and cytokine secretion upon restimulation. These distinctions showed that antigenic stimulation activated and expanded antigen-specific natural Treg cells as well as effector and memory T cells. Accordingly, FR4(hi)CD25(+)CD4(+) T cells enriched from alloantigen-stimulated T cells suppressed graft rejection. Administration of FR4 monoclonal antibody specifically reduced Treg cells, provoking effective tumor immunity in tumor-bearing animals, whereas similar treatment of normal young mice elicited autoimmune disease. Thus, specific manipulation of FR4(hi)CD25(+)CD4(+) Treg cells helps control ongoing immune responses.
Yamaguchi
Tomoyuki
T
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Hirota
Keiji
K
Nagahama
Kanji
K
Ohkawa
Katsuya
K
Takahashi
Takeshi
T
Nomura
Takeshi
T
Sakaguchi
Shimon
S
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000276:immunology*; D019556:COS Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D045744:Cell Line, Tumor; D002469:Cell Separation; D002522:Chlorocebus aethiops; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005354:Fibrosarcoma / Q000276:immunology / Q000378:metabolism; D058973:Folate Receptors, GPI-Anchored; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D008822:Mice, Transgenic; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D000941:Antigens; D002352:Carrier Proteins; D018984:Epitopes, T-Lymphocyte; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface; C543634:folate receptor 4, mouse