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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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BALB/c Ii −/−  mice are susceptible to L. major  infection and generate type 2  immune responses. (A) Groups  of fourth generation BALB/c Ii  +/− or Ii −/− and C57BL/6  (B6) Ii + or Ii +/− mice were  infected in the hind footpads  with promastigotes of L. major,  and the size of the footpad lesions measured using a metric  caliper. Data represent means  and standard deviations of footpad lesions in four separate experiments involving 12 BALB/c  Ii −/− mice. (B) Lymph node  cells were prepared from individual mice after 7 wk of infection  and were cultured with and without soluble Leishmania antigens as  described in the Materials and  Methods. After 48 h, the supernatants were assayed for IL-4 by  ELISA. Cells cultured without  antigen yielded <20 U/ml IL-4.  C57BL/6 (B6) mice are compared  to BALB/c Ii +/− and −/−  mice. Values represent means and  standard deviations of triplicate  determinations for individual animals, and are representative of  three separate experiments.
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Figure 9: BALB/c Ii −/− mice are susceptible to L. major infection and generate type 2 immune responses. (A) Groups of fourth generation BALB/c Ii +/− or Ii −/− and C57BL/6 (B6) Ii + or Ii +/− mice were infected in the hind footpads with promastigotes of L. major, and the size of the footpad lesions measured using a metric caliper. Data represent means and standard deviations of footpad lesions in four separate experiments involving 12 BALB/c Ii −/− mice. (B) Lymph node cells were prepared from individual mice after 7 wk of infection and were cultured with and without soluble Leishmania antigens as described in the Materials and Methods. After 48 h, the supernatants were assayed for IL-4 by ELISA. Cells cultured without antigen yielded <20 U/ml IL-4. C57BL/6 (B6) mice are compared to BALB/c Ii +/− and −/− mice. Values represent means and standard deviations of triplicate determinations for individual animals, and are representative of three separate experiments.

Mentions: To test this prediction, Ii −/− mice were bred four generations onto the susceptible BALB/c background, and Ii −/− and +/− littermates were infected with L. major. As assessed by monitoring of the local footpad lesions, BALB/c Ii −/− suffered disease that was comparable to Ii +/− littermates, and both differed markedly from the course of infection in concurrently infected C57BL/6 Ii −/− or Ii +/+ mice (Fig. 9 A). Quantitation of parasites recovered from the footpads and spleen corroborated the lesion measurements (data not shown). Lymph node cells recovered from infected animals and incubated with SLA in vitro generated readily recovered IL-4 that was not obtained using lymph node cells from C57BL/6 mice (Fig. 9 B). Thus, Th2 cell differentiation in vivo was also maintained in the absence of invariant chain.


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)

BALB/c Ii −/−  mice are susceptible to L. major  infection and generate type 2  immune responses. (A) Groups  of fourth generation BALB/c Ii  +/− or Ii −/− and C57BL/6  (B6) Ii + or Ii +/− mice were  infected in the hind footpads  with promastigotes of L. major,  and the size of the footpad lesions measured using a metric  caliper. Data represent means  and standard deviations of footpad lesions in four separate experiments involving 12 BALB/c  Ii −/− mice. (B) Lymph node  cells were prepared from individual mice after 7 wk of infection  and were cultured with and without soluble Leishmania antigens as  described in the Materials and  Methods. After 48 h, the supernatants were assayed for IL-4 by  ELISA. Cells cultured without  antigen yielded <20 U/ml IL-4.  C57BL/6 (B6) mice are compared  to BALB/c Ii +/− and −/−  mice. Values represent means and  standard deviations of triplicate  determinations for individual animals, and are representative of  three separate experiments.
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Figure 9: BALB/c Ii −/− mice are susceptible to L. major infection and generate type 2 immune responses. (A) Groups of fourth generation BALB/c Ii +/− or Ii −/− and C57BL/6 (B6) Ii + or Ii +/− mice were infected in the hind footpads with promastigotes of L. major, and the size of the footpad lesions measured using a metric caliper. Data represent means and standard deviations of footpad lesions in four separate experiments involving 12 BALB/c Ii −/− mice. (B) Lymph node cells were prepared from individual mice after 7 wk of infection and were cultured with and without soluble Leishmania antigens as described in the Materials and Methods. After 48 h, the supernatants were assayed for IL-4 by ELISA. Cells cultured without antigen yielded <20 U/ml IL-4. C57BL/6 (B6) mice are compared to BALB/c Ii +/− and −/− mice. Values represent means and standard deviations of triplicate determinations for individual animals, and are representative of three separate experiments.
Mentions: To test this prediction, Ii −/− mice were bred four generations onto the susceptible BALB/c background, and Ii −/− and +/− littermates were infected with L. major. As assessed by monitoring of the local footpad lesions, BALB/c Ii −/− suffered disease that was comparable to Ii +/− littermates, and both differed markedly from the course of infection in concurrently infected C57BL/6 Ii −/− or Ii +/+ mice (Fig. 9 A). Quantitation of parasites recovered from the footpads and spleen corroborated the lesion measurements (data not shown). Lymph node cells recovered from infected animals and incubated with SLA in vitro generated readily recovered IL-4 that was not obtained using lymph node cells from C57BL/6 mice (Fig. 9 B). Thus, Th2 cell differentiation in vivo was also maintained in the absence of invariant chain.

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