Functional deficit of T regulatory cells in Fulani, an ethnic group with low susceptibility to Plasmodium falciparum malaria

doi:10.1073/pnas.0709969105

Functional deficit of T regulatory cells in Fulani, an ethnic group with low susceptibility to Plasmodium falciparum malaria

*Department of Clinical Physiopathology,
^‡Center of Excellence DENOTHE, University of Firenze, Viale Pieraccini 6, 50139 Firenze, Italy;
^§Department of Public Health Sciences, University La Sapienza, Piazzale Aldo Moro 5, 00185 Rome, Italy;
^¶Centre National de Recherche et de Formation sur le Paludisme, Ministère de la Santé, BP 2208 Ouagadougou, Burkina Faso; and
^‖Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy

Edited by Robert L. Coffman, Dynavax Technologies, Berkeley, CA, and approved November 28, 2007 (received for review October 19, 2007)

Abstract

Previous interethnic comparative studies on the susceptibility to malaria performed in West Africa showed that Fulani are more resistant to Plasmodium falciparum malaria than are sympatric ethnic groups. This lower susceptibility is not associated to classic malaria-resistance genes, and the analysis of the immune response to P. falciparum sporozoite and blood stage antigens, as well as non-malaria antigens, revealed higher immune reactivity in Fulani. In the present study we compared the expression profile of a panel of genes involved in immune response in peripheral blood mononuclear cells (PBMC) from Fulani and sympatric Mossi from Burkina Faso. An increased expression of T helper 1 (TH1)-related genes (IL-18, IFNγ, and TBX21) and TH2-related genes (IL-4 and GATA3) and a reduced expression of genes distinctive of T regulatory activity (CTLA4 and FOXP3) were observed in Fulani. Microarray analysis on RNA from CD4⁺CD25⁺ (T regulatory) cells, performed with a panel of cDNA probes specific for 96 genes involved in immune modulation, indicated obvious differences between the two ethnic groups with 23% of genes, including TGFβ, TGFβRs, CTLA4, and FOXP3, less expressed in Fulani compared with Mossi and European donors not exposed to malaria. As further indications of a low T regulatory cell activity, Fulani showed lower serum levels of TGFβ and higher concentrations of the proinflammatory chemokines CXCL10 and CCL22 compared with Mossi; moreover, the proliferative response of Fulani to malaria antigens was not affected by the depletion of CD25⁺ regulatory cells whereas that of Mossi was significantly increased. The results suggest that the higher resistance to malaria of the Fulani could derive from a functional deficit of T regulatory cells.

Footnotes

^†To whom correspondence may be addressed. E-mail: g.torcia{at}dfc.unifi.it, l.cosmi{at}dmi.unifi.it, or david.modiano{at}uniroma1.it
Author contributions: M.G.T. and V.S. contributed equally to this work; M.G.T., L.C., F.A., and D.M. designed research; M.G.T., V.S., L.C., A.C., L.M., V.D.M., F.V., G.B., I.N., B.S.S., F.L., F.F., R.A., F.A., and D.M. performed research; C.S. and A.R.S. contributed new reagents/analytic tools; P.B., M.L., E.M., E.G., M.C., F.C., and S.R. analyzed data; and M.G.T. and D.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0709969105/DC1.
Freely available online through the PNAS open access option.