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Infection and Immunity, May 2003, p. 2674-2683, Vol. 71, No. 5
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.5.2674-2683.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Levels and Patterns of Cytokines Produced by CD4 T Lymphocytes of BALB/c Mice Infected with Leishmania major by Inoculation into the Ear Dermis Depend on the Infectiousness and Size of the Inoculum

Thierry Lang,^* Nathalie Courret, Jean-Hervé Colle, Geneviève Milon, and Jean-Claude Antoine

Unité d'Immunophysiologie et Parasitisme Intracellulaire, Institut Pasteur, Paris, France

Received 16 July 2002/ Returned for modification 11 September 2002/ Accepted 12 February 2003

The production of cytokines by CD4 lymph node T lymphocytes derived from BALB/c mice recently infected in the ear dermis with high (10⁶ parasites) or low (10³ parasites) doses of Leishmania major metacyclic promastigotes (MP) was examined over a 3-week period following inoculation. Results were compared with those obtained when mice were injected with less infectious parasite populations, namely, stationary-phase or log-phase promastigotes (LP). Cells were purified 16 h and 3, 8, and 19 days after inoculation, and the amounts of gamma interferon (IFN-) and interleukin-4 (IL-4) released in response to LACK (Leishmania homolog of receptors for activated C kinase) or total L. major antigens were assessed. We found that LACK-reactive T cells from mice inoculated with a high dose of parasites first produced IFN- and later on IL-4; the level of IFN- produced early by these cells was dependent upon the stage of the promastigotes inoculated, the highest level being reached with cells recovered from mice inoculated with the least infectious parasites, LP; sequential production of IFN- and then of IL-4 also characterized L. major antigen-reactive CD4 T cells, suggesting that the early production of IFN- does not impede the subsequent rise of IL-4 and finally the expansion of the parasites; after low-dose inoculation of MP, cutaneous lesions developed with kinetics similar to that of lesions induced after inoculation of 10⁶ LP, but in this case CD4 T lymphocytes did not release IFN- or IL-4 in the presence of LACK and neither cytokine was produced in response to L. major antigens before the onset of lesion signs. These results suggest the existence of a discreet phase in terms of CD4 T-cell reactivity for at least the first 8 days following inoculation, a time period during which parasites are able to grow moderately. In conclusion, the levels and profiles of cytokines produced by Leishmania-specific CD4 T lymphocytes clearly depend on both the stage of differentiation and number of parasites used for inoculation.

Editor: S. H. E. Kaufmann

Present address: Département des Maladies Infectieuses, Institut Cochin, 75014 Paris, France.

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