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A role for CD4 in peripheral T cell differentiation.

Brown DR, Moskowitz NH, Killeen N, Reiner SL - J. Exp. Med. (1997)

Bottom Line: CD4 serves a prominent role in potentiating antigen recognition by helper T cells.Together, these results demonstrate a previously undescribed role of the CD4 molecule.The requirement for CD4 in Th2 maturation reflects the importance of molecules other than cytokines in the control of helper T cell differentiation.

View Article: PubMed Central - PubMed

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

ABSTRACT
Naive CD4+ T helper cells (Th) differentiate into one of two well-defined cell types during immune responses. Mature Th1 and Th2 cells regulate the type of response as a consequence of the unique cytokines that they secrete. CD4 serves a prominent role in potentiating antigen recognition by helper T cells. We have examined the role of CD4 in peripheral T cell differentiation by studying helper T cells from mice with a congenital defect in CD4 expression. After protein immunization or infection with Leishmania major, CD4-deficient mice were incapable of mounting antigen-specific Th2 responses, but retained their Th1 potency. CD4-deficient, T cell receptor transgenic T cells were also incapable of Th2 differentiation after in vitro activation. Expression of a wild-type CD4 transgene corrected the Th2 defect of CD4-deficient mice in all immune responses tested. To investigate the role of the cytoplasmic domain, mice reconstituted with a truncated CD4 molecule were also studied. Expression of the tailless CD4 transgene could not rescue the Th2 defect of CD4-deficient mice immunized with protein or CD4-deficient transgenic T cells activated in vitro, raising the possibility that the cytoplasmic domain of CD4 may influence Th2 generation. Expression of the tailless transgene was, however, capable of restoring Th2 development in CD4-deficient mice infected with L. major or CD4-deficient transgenic T cells activated in the presence of recombinant IL-4, demonstrating that the cytoplasmic domain is not absolutely required for Th2 development. Together, these results demonstrate a previously undescribed role of the CD4 molecule. The requirement for CD4 in Th2 maturation reflects the importance of molecules other than cytokines in the control of helper T cell differentiation.

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The cytoplasmic domain of CD4 is not essential for susceptibility or Th2 responses after L. major infection. (A) BALB/c CD4° and  CD4° transgene-reconstituted mice (CD4°CD4WT, CD4°CD4Δcyt) were  infected with L. major as described in Materials and Methods. The results  shown are the mean footpad measurements of groups of two animals each  and are representative of five separate experiments using 9 CD4°CD4WT  and 11 CD4°CD4Δcyt mice. (B) Popliteal lymph node cells from infected  BALB/c CD4° (−) and CD4° transgene-reconstituted mice (WT, Δcyt)  were analyzed for parasite-specific cytokine secretion after restimulation  in vitro. The results shown are the mean of triplicate determinations from  individual mice, and are representative of four separate experiments using  eight CD4WT and nine CD4Δcyt mice.
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Figure 8: The cytoplasmic domain of CD4 is not essential for susceptibility or Th2 responses after L. major infection. (A) BALB/c CD4° and CD4° transgene-reconstituted mice (CD4°CD4WT, CD4°CD4Δcyt) were infected with L. major as described in Materials and Methods. The results shown are the mean footpad measurements of groups of two animals each and are representative of five separate experiments using 9 CD4°CD4WT and 11 CD4°CD4Δcyt mice. (B) Popliteal lymph node cells from infected BALB/c CD4° (−) and CD4° transgene-reconstituted mice (WT, Δcyt) were analyzed for parasite-specific cytokine secretion after restimulation in vitro. The results shown are the mean of triplicate determinations from individual mice, and are representative of four separate experiments using eight CD4WT and nine CD4Δcyt mice.

Mentions: The association of CD4 with p56lck has been implicated in signaling and in the recruitment of CD4 to the TCR complex (20, 21). To study the role of this association in the potentiation of the Th2 fate, we used transgenic mice expressing wild-type CD4 (CD4WT) or a mutant lacking the cytoplasmic tail (CD4Δcyt). Both of these transgenes are capable of rescuing helper T cell development in CD4° mice, although overexpression of the tailless version is required for this effect (15). CD4WT and CD4Δcyt transgenic mice were backcrossed onto the BALB/c background and then intercrossed with CD4° mice expressing the OVA-specific transgenic TCR. The CD4WT transgene corrected the Th2 defect when expressed in CD4° OVA-specific T cells, but the CD4Δcyt transgene was ineffective in promoting the Th2 fate (Fig. 6). When exogenous rIL-4 was added to the primary culture, however, either transgene was capable of reconstituting Th2 induction (Fig. 6). Similar results were observed in vivo. The CD4WT transgene rescued the Th2 response to KLH immunization, whereas the CD4Δcyt transgene did not (Fig. 7). Both types of transgenes, however, restored susceptibility (Fig. 8 A) and Th2 responses (Fig. 8 B) to leishmaniasis in BALB/c CD4° mice. Thus, the Th2 defect caused by a mutation in the CD4 gene can be fully corrected by ectopic expression of wild-type CD4, and partially corrected by a mutant form that lacks the cytoplasmic domain.


A role for CD4 in peripheral T cell differentiation.

Brown DR, Moskowitz NH, Killeen N, Reiner SL - J. Exp. Med. (1997)

The cytoplasmic domain of CD4 is not essential for susceptibility or Th2 responses after L. major infection. (A) BALB/c CD4° and  CD4° transgene-reconstituted mice (CD4°CD4WT, CD4°CD4Δcyt) were  infected with L. major as described in Materials and Methods. The results  shown are the mean footpad measurements of groups of two animals each  and are representative of five separate experiments using 9 CD4°CD4WT  and 11 CD4°CD4Δcyt mice. (B) Popliteal lymph node cells from infected  BALB/c CD4° (−) and CD4° transgene-reconstituted mice (WT, Δcyt)  were analyzed for parasite-specific cytokine secretion after restimulation  in vitro. The results shown are the mean of triplicate determinations from  individual mice, and are representative of four separate experiments using  eight CD4WT and nine CD4Δcyt mice.
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Related In: Results  -  Collection

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Figure 8: The cytoplasmic domain of CD4 is not essential for susceptibility or Th2 responses after L. major infection. (A) BALB/c CD4° and CD4° transgene-reconstituted mice (CD4°CD4WT, CD4°CD4Δcyt) were infected with L. major as described in Materials and Methods. The results shown are the mean footpad measurements of groups of two animals each and are representative of five separate experiments using 9 CD4°CD4WT and 11 CD4°CD4Δcyt mice. (B) Popliteal lymph node cells from infected BALB/c CD4° (−) and CD4° transgene-reconstituted mice (WT, Δcyt) were analyzed for parasite-specific cytokine secretion after restimulation in vitro. The results shown are the mean of triplicate determinations from individual mice, and are representative of four separate experiments using eight CD4WT and nine CD4Δcyt mice.
Mentions: The association of CD4 with p56lck has been implicated in signaling and in the recruitment of CD4 to the TCR complex (20, 21). To study the role of this association in the potentiation of the Th2 fate, we used transgenic mice expressing wild-type CD4 (CD4WT) or a mutant lacking the cytoplasmic tail (CD4Δcyt). Both of these transgenes are capable of rescuing helper T cell development in CD4° mice, although overexpression of the tailless version is required for this effect (15). CD4WT and CD4Δcyt transgenic mice were backcrossed onto the BALB/c background and then intercrossed with CD4° mice expressing the OVA-specific transgenic TCR. The CD4WT transgene corrected the Th2 defect when expressed in CD4° OVA-specific T cells, but the CD4Δcyt transgene was ineffective in promoting the Th2 fate (Fig. 6). When exogenous rIL-4 was added to the primary culture, however, either transgene was capable of reconstituting Th2 induction (Fig. 6). Similar results were observed in vivo. The CD4WT transgene rescued the Th2 response to KLH immunization, whereas the CD4Δcyt transgene did not (Fig. 7). Both types of transgenes, however, restored susceptibility (Fig. 8 A) and Th2 responses (Fig. 8 B) to leishmaniasis in BALB/c CD4° mice. Thus, the Th2 defect caused by a mutation in the CD4 gene can be fully corrected by ectopic expression of wild-type CD4, and partially corrected by a mutant form that lacks the cytoplasmic domain.

Bottom Line: CD4 serves a prominent role in potentiating antigen recognition by helper T cells.Together, these results demonstrate a previously undescribed role of the CD4 molecule.The requirement for CD4 in Th2 maturation reflects the importance of molecules other than cytokines in the control of helper T cell differentiation.

View Article: PubMed Central - PubMed

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

ABSTRACT
Naive CD4+ T helper cells (Th) differentiate into one of two well-defined cell types during immune responses. Mature Th1 and Th2 cells regulate the type of response as a consequence of the unique cytokines that they secrete. CD4 serves a prominent role in potentiating antigen recognition by helper T cells. We have examined the role of CD4 in peripheral T cell differentiation by studying helper T cells from mice with a congenital defect in CD4 expression. After protein immunization or infection with Leishmania major, CD4-deficient mice were incapable of mounting antigen-specific Th2 responses, but retained their Th1 potency. CD4-deficient, T cell receptor transgenic T cells were also incapable of Th2 differentiation after in vitro activation. Expression of a wild-type CD4 transgene corrected the Th2 defect of CD4-deficient mice in all immune responses tested. To investigate the role of the cytoplasmic domain, mice reconstituted with a truncated CD4 molecule were also studied. Expression of the tailless CD4 transgene could not rescue the Th2 defect of CD4-deficient mice immunized with protein or CD4-deficient transgenic T cells activated in vitro, raising the possibility that the cytoplasmic domain of CD4 may influence Th2 generation. Expression of the tailless transgene was, however, capable of restoring Th2 development in CD4-deficient mice infected with L. major or CD4-deficient transgenic T cells activated in the presence of recombinant IL-4, demonstrating that the cytoplasmic domain is not absolutely required for Th2 development. Together, these results demonstrate a previously undescribed role of the CD4 molecule. The requirement for CD4 in Th2 maturation reflects the importance of molecules other than cytokines in the control of helper T cell differentiation.

Show MeSH
Related in: MedlinePlus