Resistance to murine cutaneous leishmaniasis is mediated by T_H1 cells, but disease‐promoting CD4⁺ cells are different from T_H2 cells

Abstract

A limiting dilution system has been used for quantitative analysis of antigen‐reactive T cells producing interleukin (IL)2, IL4 and interferon (IFN)‐γ in the course of murine infection with Leishmania major. The precursor frequencies of CD4+ cells with the potential for production of IFN‐γ, which has been associated with TH1 cells, are much higher in resistant than in susceptible mice, whereas the reverse is found for CD4+ cells secreting IL4 which have been classified as TH2 cells. Our results allow a better understanding of the relative contribution of these cell types at various stages of disease and can be summarized as follows: (a) secretion of IL4 can be demonstrated in short‐term clonal cultures of CD4+ cells from L. major‐infected mice, (b) CD4+ cells releasing IL2, suggested to be a characteristic of TH1 cells that predominate in resistant mice, can also be detected in susceptible mice at any time of infection, (c) both IL2 and IL4 are released by the progeny of individual T cells from susceptible mice and (d) the kinetics of precursor frequencies in genetically susceptible mice protected against the disease by prophylactic treatment are different from those of congenitally resistant mice, thus indicating that the development of lymphokine‐producing T cells and the establishment of protective immunity may be regulated differently in those mice. The data suggest that resistance to disease is correlated with the presence of IFN‐γ‐producing TH1 cells, while susceptibility is associated with CD4+ cells that do not segregate into the TH1 or TH2 subset but display an overlapping pattern of lymphokine activities.

The protective Th1 response in mice is induced in the T-cell zone only three weeks after infection with Leishmania major and not during early T-cell activation

“…Our result is in contrast to other studies which demonstrate that the Th1/Th2 differentiation is induced within the first days of infection [4,5,11,26]. One reason for this controversy could be the technical approach used in these studies.…”

“…The concept that cytokines present at the time of CD4 T-cell activation mediate the developmental switch to either Th1 or Th2 effector cells was based on observations of long-term cultured CD4 T-cell clones [3]. Accordingly, it has been shown in in vitro studies that the Th1/Th2 differentiation is induced within the first 3 days after L. major infection [4,5]. Other reports found no difference in the expression of IL12p40 and IFNc early after L. major infection between resistant C57BL/6 mice and susceptible BALB/c mice [6][7][8].…”

Immunobiology of experimental leishmaniasis

“…Finally, while resistance is correlated with a TH 1 phenotype of antigen-reactive CD4 + T cells, there are some indications that susceptibility can be associated with CD4 + T cells expressing more than one pattern of lymphokine secretion, as shown in a limiting dilution system [47]. Data obtained using L. major-specific T cell clones and lines also support the notion that some antigen-specific TH 1 T cells are not protective and can even exacerbate disease [53,79].…”

Perforin and Gamma Interferon Are Critical CD8+T-Cell-Mediated Responses in Vaccine-Induced Immunity againstLeishmania amazonensisInfection

“…LN cells from P-8-immunized and infected mice were cultured in the absence of antigen to confirm that the IFN-␥ produced was indeed antigen specific. Minimal estimates of the frequency of P-8-responding cells were obtained by methods previously described (40).…”