Resistance to Leishmania major in mice.

to Leishmania major in mice is a topic of interest to many imMLunologists attempting to link the immunological mechanism with the responsible genes. In this respect, this experimental system is one of the paradigms for genetics of disease susceptibility. Mehmet L. Giuler et al. (1) question the hypothesis that production of interleUkin-4 (IL-4) with subsequent generation of a T helper cell type 2 (TH2) response is the cause of susceptibility of BALB/c mice to L. major infection. Their data show that the susceptible BALB/c mice, but not the resistant B1O.D2 mice, exhibit a diminished induction of interferon y (IFN--y) by IL-12 treatment, indicating a deficient TH1 response, whereas the IL-4 response is the same in both strains. This deficit in the THI response in BALB/c mice is linked to a region of chromosome 11 comprising IL-4, IRF-1, and several other immunologically relevant loci. Gtiler et al. propose that their findings are relevant for the host response to L. major infection because of the linkage between this chromosomal region and susceptibility to L. major suggested by Roberts et al. (2). They propose, therefore, that the resistance to L. major is based on maintenance of the IL-12 pathway and not on differential regulation of IL-4 production. The genetic data argue against this simple model. We analyzed the genetic differences in T cell activation and resistance to L. major between the susceptible strain BALB/ cHeA and the resistant strain STS/A using the series of 20 homozygous CcS/Dem recombinant congenic (RC) strains. Each of the CcS/Dem strains carries a different random set of approximately 12.5% of the genes of the STS/A strain on the genetic background of the BALB/cHeA strain. Consequently, the individual loci involved in control of a multigenic trait were separated into different CcS/Dem strains, where they could be studied one by one (3). Our testing of susceptibility to L. major in the 20 CcS/Dem strains indicates that it is multigenically controlled (4). Moreover, the most resistant RC strain, CcS-5, received the whole central and telomeric part of chromosome 11 (including the IL-4 locus and the other linked immunologically relevant loci) from the susceptible parent BALB/c (5), indicating that this region cannot be the major factor determining susceptibility of BALB/c mice. Even in the case that this region of chromosome 11 has some effect on L. major susceptibility, it has by no means been proven that this effect is based on the IL12 response. We found that the quantitative differences in proliferative T cell response to TCR-mediated activation is also closely linked to this region (6). This indicates that responsiveness to a variety of cytokines driving T cell proliferation (including IL-2, which we have tested separately) is controlled by this genetic region. Therefore, GOler et al. cannot pinpoint the control of susceptibility to L. major to IL-12 responsiveness only, because other cytokines and receptors may be involved as well. Thus, the claim that the genetic deficit of TH1 response is the major cause of susceptibility to L. major cannot be maintained on the basis of the currently available data. Taking into consideration that the susceptibility of BALB/c mice is determined by several genes, it is unlikely that the reported difference is based on a single step of the immune response. Peter Demant Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands E-mail: demant@nki.nl Marie Lipoldova Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Plemingovo nam. 2, 16637, Prague 6, Czech Republic E-mail: marie.lipoldova@img.cas. cz Milena Svobodova Department of Parasitology, Charles University, Vinicna 7, 128 44 Prague 2, Czech Republic E-mail: kulda@csearn.bitnet