CTLA-4 in filarial infections: implications for a role in diminished T cell reactivity.
To determine the role that CTLA-4 might play in mediating the diminished parasite Ag-specific T cell responsiveness that is characteristically seen in filaria-infected patients, several study populations and methods were used. First, quantitative assessment of mRNA expression determined that PBMC from uninfected adolescents exposed in utero to microfilarial (Mf) Ag demonstrated a strong up-regulation of CTLA-4 to the Mf stage of the parasite in contrast to that observed in cells from children born of uninfected mothers (p = 0.005). Next, the frequency of CTLA-4 expression was examined using flow cytometry in cells from filaria-infected and -uninfected individuals ex vivo. Individuals born in filarial endemic regions of the world (with long-standing infections) had greater percentages of CD4(+)CTLA-4(+) cells than did expatriate infected or uninfected individuals (p = 0.005 and 0.05, respectively); in addition, Mf(+) patients demonstrated higher frequencies of CD4(+)CTLA-4(+) and CD8(+)CTLA-4(+) cells (p = 0.027 and 0.037, respectively) than did Mf(-) infected individuals. Of interest, the greatest intensity of CTLA-4 expression occurred in CD4(+)CD25(+) cells, a population purported to include suppressor cells. Finally, in vitro blocking of CTLA-4 expression in PBMC from filaria-infected individuals induced a mean increase of 44% in IL-5 production to Mf Ag, whereas there was a concurrent mean decrease of 42% in IFN-gamma production, suggesting that CTLA-4 also acts to alter the Th1/Th2 balance in filaria-infected individuals. Together, these data indicate a significant role for CTLA-4 in regulating the host response to filarial infections and that factors such as length of exposure and patency are important codeterminants.
Steel
Cathy
C
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 4 Center Drive, Room 4/126, Bethesda, MD 20892. csteel@niaid.nih.gov
Nutman
Thomas B
TB
D000069594:Abatacept; D000293:Adolescent; D000328:Adult; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D000947:Antigens, Helminth / Q000276:immunology; D017178:Brugia malayi / Q000276:immunology; D018106:CD28 Antigens / Q000096:biosynthesis; D060908:CTLA-4 Antigen; D005260:Female; D005368:Filariasis / Q000276:immunology* / Q000635:transmission; D006801:Humans; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D008842:Microfilariae / Q000254:growth & development / Q000276:immunology; D008875:Middle Aged; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000469:parasitology; D014958:Wuchereria bancrofti / Q000254:growth & development / Q000276:immunology
D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000947:Antigens, Helminth; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D007166:Immunosuppressive Agents; D000069594:Abatacept