Flow Cytometric Determination of Cellular Sources and Frequencies of Key Cytokine-Producing Lymphocytes Directed against Recombinant LACK and Soluble Leishmania Antigen in Human Cutaneous Leishmaniasis

doi:10.1128/IAI.69.5.3232-3239.2001

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Infection and Immunity, May 2001, p. 3232-3239, Vol. 69, No. 5
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.5.3232-3239.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Flow Cytometric Determination of Cellular Sources and Frequencies of Key Cytokine-Producing Lymphocytes Directed against Recombinant LACK and Soluble Leishmania Antigen in Human Cutaneous Leishmaniasis

R. L. A. Bottrel,¹ W. O. Dutra,² F. A. Martins,¹ B. Gontijo,³ E. Carvalho,⁴ M. Barral-Netto,⁴^,⁵ A. Barral,⁴^,⁵ R. P. Almeida,⁴ W. Mayrink,⁶ R. Locksley,⁷ and K. J. Gollob¹^,^*

Department of Biochemistry-Immunology,¹ Department of Morphology,² and Department of Parasitology,⁶ Universidade Federal de Minas Gerais (UFMG) and UFMG Medical Center,³ Belo Horizonte, Minas Gerais, UFBA Medical Center,⁴ and CPqGM-FIOCRUZ,⁵ Salvador, Bahia, Brazil, and UCSF Medical Center, San Francisco, California⁷

Received 4 December 2000/Returned for modification 27 January 2001/Accepted 11 February 2001

Leishmaniasis, caused by infection with the protozoan parasite Leishmania, affects millions of individuals worldwide, causingserious morbidity and mortality. This study directly determinedthe frequency of cells producing key immunoregulatory cytokinesin response to the recombinant antigen Leishmania homolog of receptorsfor activated kinase C (LACK) and soluble leishmania antigen (SLA),and it determined relative contributions of these antigens tothe overall cytokine profile in individuals infected for the firsttime with Leishmania braziliensis. All individuals presented withthe cutaneous clinical form of leishmaniasis and were analyzedfor proliferative responses to LACK antigen and SLA, frequencyof lymphocyte subpopulations (analyzed ex vivo), and antigen-induced(LACK and SLA) cytokine production at the single-cell level (determinedby flow cytometry). The following were determined. (i) The Th1-typeresponse previously seen in patients with cutaneous leishmaniasisis due to gamma interferon (IFN- $gamma$ ) production by several differentsources, listed in order of contribution: CD4⁺ T lymphocytes, CD4, CD8 lymphocytes, and CD8⁺ T lymphocytes. (ii) SLA induced a higher frequency of lymphocytesproducing IFN- $gamma$ and tumor necrosis factor alpha (TNF- $alpha$ ) than didLACK. (iii) LACK induced an activation of monocyte populationsas reflected by an increased percentage of CD14-positive cells.(iv) Neither SLA nor LACK induced detectable frequencies of cellsproducing interleukin-4 (IL-4) or IL-5. These data demonstrateda multifaceted immune response to SLA in human leishmaniasis involvingTh1 CD4⁺ T lymphocytes (IFN- $gamma$ ⁺ and IL-10/IL-4), Tc1 CD8⁺ T cells (IFN- $gamma$ ⁺, and IL-10/IL-4), and a high frequency of TNF- $alpha$ -producing lymphocytes. Moreover,it was determined that the recombinant antigen LACK acts as aweak inducer of Th1-type lymphocyte responses compared toSLA.

^* Corresponding author. Mailing address: Federal University of Minas Gerais, Institute of Biological Sciences, Department ofBiochemistry-Immunology, Av. Antonio Carlos, 6627, C.P. 486, BeloHorizonte, MG, 30161-970, Brazil. Phone and Fax: 55-31-3499-2655.E-mail: kjgollob{at}mono.icb.ufmg.br.

Infection and Immunity, May 2001, p. 3232-3239, Vol. 69, No. 5
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.5.3232-3239.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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