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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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IFN-γ production is maintained in infected Ii −/− mice,  despite suboptimal proliferation. Lymph node cells were prepared from  Ii +/− or −/− mice infected 8 wk before with L. major, and incubated  with or without soluble Leishmania antigens as described in the Materials  and Methods. After 48 h, supernatants were collected and assayed for the  presence of IFN-γ by ELISA (right). After 72 h, wells were pulsed with  1 μCi[3H]thymidine, and the cells harvested 16 h later to measure incorporation of radioactivity. Data points on the left represent results in the  absence of antigen, and on the right, in the presence of antigen. Data represent three individual mice from each group, and are representative of  three separate experiments. Values are means and standard deviations of  triplicate determinations.
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Figure 4: IFN-γ production is maintained in infected Ii −/− mice, despite suboptimal proliferation. Lymph node cells were prepared from Ii +/− or −/− mice infected 8 wk before with L. major, and incubated with or without soluble Leishmania antigens as described in the Materials and Methods. After 48 h, supernatants were collected and assayed for the presence of IFN-γ by ELISA (right). After 72 h, wells were pulsed with 1 μCi[3H]thymidine, and the cells harvested 16 h later to measure incorporation of radioactivity. Data points on the left represent results in the absence of antigen, and on the right, in the presence of antigen. Data represent three individual mice from each group, and are representative of three separate experiments. Values are means and standard deviations of triplicate determinations.

Mentions: The unusual intracellular compartment occupied by Leishmania amastigotes raised the possibility that peptides from the organisms might normally access class II in an Ii-independent manner. However, we found that antigen-induced proliferation of lymph node cells taken from infected animals was significantly impaired in Ii −/−, as compared to I +/−, mice, demonstrating substantial Ii-dependence for optimal antigen presentation (Fig. 4). Assays using the same groups of cells showed comparable levels of antigen-induced IFN-γ, revealing dissociation of these two lymphocyte activities under the conditions used (Fig. 4).


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)

IFN-γ production is maintained in infected Ii −/− mice,  despite suboptimal proliferation. Lymph node cells were prepared from  Ii +/− or −/− mice infected 8 wk before with L. major, and incubated  with or without soluble Leishmania antigens as described in the Materials  and Methods. After 48 h, supernatants were collected and assayed for the  presence of IFN-γ by ELISA (right). After 72 h, wells were pulsed with  1 μCi[3H]thymidine, and the cells harvested 16 h later to measure incorporation of radioactivity. Data points on the left represent results in the  absence of antigen, and on the right, in the presence of antigen. Data represent three individual mice from each group, and are representative of  three separate experiments. Values are means and standard deviations of  triplicate determinations.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: IFN-γ production is maintained in infected Ii −/− mice, despite suboptimal proliferation. Lymph node cells were prepared from Ii +/− or −/− mice infected 8 wk before with L. major, and incubated with or without soluble Leishmania antigens as described in the Materials and Methods. After 48 h, supernatants were collected and assayed for the presence of IFN-γ by ELISA (right). After 72 h, wells were pulsed with 1 μCi[3H]thymidine, and the cells harvested 16 h later to measure incorporation of radioactivity. Data points on the left represent results in the absence of antigen, and on the right, in the presence of antigen. Data represent three individual mice from each group, and are representative of three separate experiments. Values are means and standard deviations of triplicate determinations.
Mentions: The unusual intracellular compartment occupied by Leishmania amastigotes raised the possibility that peptides from the organisms might normally access class II in an Ii-independent manner. However, we found that antigen-induced proliferation of lymph node cells taken from infected animals was significantly impaired in Ii −/−, as compared to I +/−, mice, demonstrating substantial Ii-dependence for optimal antigen presentation (Fig. 4). Assays using the same groups of cells showed comparable levels of antigen-induced IFN-γ, revealing dissociation of these two lymphocyte activities under the conditions used (Fig. 4).

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