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T helper subset differentiation in the absence of invariant chain.

Brown DR, Swier K, Moskowitz NH, Naujokas MF, Locksley RM, Reiner SL - J. Exp. Med. (1997)

Bottom Line: We wished to determine whether this unexpected efficiency of T helper subset induction despite inefficient T cell stimulation could be modeled in vitro.In the presence of rIL-12 or rIL-4 naive parasite-specific transgenic T cells could mature into IFN-gamma-or IL-4-secreting T helper cells, respectively, even when antigen presentation was suboptimal or antigen dose was submitogenic.These experiments demonstrate that activation of T helper cells to a threshold required for IL-2 production or proliferation is not required to achieve induction of disease-regulating T helper cell effector functions, and that pathogen-associated secondary activation signals may facilitate the full differentiation of T helper subsets during limiting presentation of antigenic peptides.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Gwen Knapp Center for Lupus & Immunology Research, University of Chicago, Illinois 60637, USA.

ABSTRACT
The outcome of murine infection with Leishmania major is regulated by major histocompatibility complex class II-restricted T helper cells. Invariant chain-deficient (Ii -/-) mice have impaired ability to present major histocompatibility complex class II-restricted antigens, and reduced numbers of CD4+ T cells. Despite these deficits, C57BL/6 Ii -/- mice controlled L. major infection comparably to wild-type mice. As assessed by mRNA analysis and in vitro antigen restimulation for IFN-gamma, Ii -/- mice had normal induction of Th1 subset differentiation even though antigen-dependent proliferation of their lymph node cells was substantially compromised. In addition, BALB/c Ii -/- mice exhibited a progressive course of infection and Th2 effector cell development that were comparable to that seen in wild-type BALB/c mice. We wished to determine whether this unexpected efficiency of T helper subset induction despite inefficient T cell stimulation could be modeled in vitro. In the presence of rIL-12 or rIL-4 naive parasite-specific transgenic T cells could mature into IFN-gamma-or IL-4-secreting T helper cells, respectively, even when antigen presentation was suboptimal or antigen dose was submitogenic. These experiments demonstrate that activation of T helper cells to a threshold required for IL-2 production or proliferation is not required to achieve induction of disease-regulating T helper cell effector functions, and that pathogen-associated secondary activation signals may facilitate the full differentiation of T helper subsets during limiting presentation of antigenic peptides.

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Resistance in Ii −/−  mice represents control of parasite  growth in tissues. Cohorts of  C57BL/6 Ii −/− or Ii +/− mice,  together with class II −/− and  susceptible BALB/c mice, were  infected with L. major and, after 8  wk, the popliteal lymph nodes and  spleens were homogenized in  equivalent volumes of media and  serially diluted into growth media  that supported the conversion of  intracellular organisms to the  extracellular promastigotes. Wells  were examined 2 wk later for  motile promastigotes using inverted microscopy.
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Figure 2: Resistance in Ii −/− mice represents control of parasite growth in tissues. Cohorts of C57BL/6 Ii −/− or Ii +/− mice, together with class II −/− and susceptible BALB/c mice, were infected with L. major and, after 8 wk, the popliteal lymph nodes and spleens were homogenized in equivalent volumes of media and serially diluted into growth media that supported the conversion of intracellular organisms to the extracellular promastigotes. Wells were examined 2 wk later for motile promastigotes using inverted microscopy.

Mentions: To confirm that measurements of the local lesions correlated with tissue parasite burdens, dilutions of footpad and spleen were incubated in vitro and the numbers of recovered parasites were quantitated microscopically (Fig. 2). Although there was some variability among experiments, Ii −/− mice had comparable or even lower numbers of recovered organisms than Ii +/− mice in both tissues. Both Ii −/− and +/− mice, however, had significantly lower numbers of parasites than genetically susceptible BALB/c mice. The capacity of the Ii −/− mice to control L. major contrasted sharply with the inability of class II −/− mice to resist infection. These latter mice demonstrated unrestrained progression of the local lesion and large numbers of parasites in the footpad and spleen after 8 wk of infection (Fig. 2).


T helper subset differentiation in the absence of invariant chain.

Brown DR, Swier K, Moskowitz NH, Naujokas MF, Locksley RM, Reiner SL - J. Exp. Med. (1997)

Resistance in Ii −/−  mice represents control of parasite  growth in tissues. Cohorts of  C57BL/6 Ii −/− or Ii +/− mice,  together with class II −/− and  susceptible BALB/c mice, were  infected with L. major and, after 8  wk, the popliteal lymph nodes and  spleens were homogenized in  equivalent volumes of media and  serially diluted into growth media  that supported the conversion of  intracellular organisms to the  extracellular promastigotes. Wells  were examined 2 wk later for  motile promastigotes using inverted microscopy.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196096&req=5

Figure 2: Resistance in Ii −/− mice represents control of parasite growth in tissues. Cohorts of C57BL/6 Ii −/− or Ii +/− mice, together with class II −/− and susceptible BALB/c mice, were infected with L. major and, after 8 wk, the popliteal lymph nodes and spleens were homogenized in equivalent volumes of media and serially diluted into growth media that supported the conversion of intracellular organisms to the extracellular promastigotes. Wells were examined 2 wk later for motile promastigotes using inverted microscopy.
Mentions: To confirm that measurements of the local lesions correlated with tissue parasite burdens, dilutions of footpad and spleen were incubated in vitro and the numbers of recovered parasites were quantitated microscopically (Fig. 2). Although there was some variability among experiments, Ii −/− mice had comparable or even lower numbers of recovered organisms than Ii +/− mice in both tissues. Both Ii −/− and +/− mice, however, had significantly lower numbers of parasites than genetically susceptible BALB/c mice. The capacity of the Ii −/− mice to control L. major contrasted sharply with the inability of class II −/− mice to resist infection. These latter mice demonstrated unrestrained progression of the local lesion and large numbers of parasites in the footpad and spleen after 8 wk of infection (Fig. 2).

Bottom Line: We wished to determine whether this unexpected efficiency of T helper subset induction despite inefficient T cell stimulation could be modeled in vitro.In the presence of rIL-12 or rIL-4 naive parasite-specific transgenic T cells could mature into IFN-gamma-or IL-4-secreting T helper cells, respectively, even when antigen presentation was suboptimal or antigen dose was submitogenic.These experiments demonstrate that activation of T helper cells to a threshold required for IL-2 production or proliferation is not required to achieve induction of disease-regulating T helper cell effector functions, and that pathogen-associated secondary activation signals may facilitate the full differentiation of T helper subsets during limiting presentation of antigenic peptides.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Gwen Knapp Center for Lupus & Immunology Research, University of Chicago, Illinois 60637, USA.

ABSTRACT
The outcome of murine infection with Leishmania major is regulated by major histocompatibility complex class II-restricted T helper cells. Invariant chain-deficient (Ii -/-) mice have impaired ability to present major histocompatibility complex class II-restricted antigens, and reduced numbers of CD4+ T cells. Despite these deficits, C57BL/6 Ii -/- mice controlled L. major infection comparably to wild-type mice. As assessed by mRNA analysis and in vitro antigen restimulation for IFN-gamma, Ii -/- mice had normal induction of Th1 subset differentiation even though antigen-dependent proliferation of their lymph node cells was substantially compromised. In addition, BALB/c Ii -/- mice exhibited a progressive course of infection and Th2 effector cell development that were comparable to that seen in wild-type BALB/c mice. We wished to determine whether this unexpected efficiency of T helper subset induction despite inefficient T cell stimulation could be modeled in vitro. In the presence of rIL-12 or rIL-4 naive parasite-specific transgenic T cells could mature into IFN-gamma-or IL-4-secreting T helper cells, respectively, even when antigen presentation was suboptimal or antigen dose was submitogenic. These experiments demonstrate that activation of T helper cells to a threshold required for IL-2 production or proliferation is not required to achieve induction of disease-regulating T helper cell effector functions, and that pathogen-associated secondary activation signals may facilitate the full differentiation of T helper subsets during limiting presentation of antigenic peptides.

Show MeSH
Related in: MedlinePlus