Polarization of Naive CD4+ T Cells Toward the Th1 Subset by CTLA-4 Costimulation

108

In the present study, we show that human self-MHC-reactive (autoreactive) T cell clones are functionally distinct from Ag-specific T cell clones. Self-MHC-reactive T cells exhibited helper function for B cell Ig production when cultured with non-T cells alone, and they exhibit suppressor function when cultured with PWM- or rCD40 ligand (rCD40L)-activated non-T cells, whereas tetanus toxoid (TT)-specific clones exhibited only helper function in the presence of TT with or without PWM or rCD40L. Addition of neutralizing Abs to the cultures showed that the suppression was mediated by TGF-β but not by IL-10 or IFN-γ. The self-MHC-reactive clones also inhibited proliferation of primary CD4+ T cells and TT-specific T cell clones, but in this case the inhibition was mediated by both IL-10 and TGF-β. In further studies, the interactions between self-MHC-reactive T cell clones and non-T cells that led to suppressor cytokine production have been explored. We found that prestimulation of non-T cells for 8 h with PWM or for 48 h for rCD40L results in non-T cells capable of inducing self-MHC-reactive T cell to produce high levels of TGF-β and IL-10. In addition, these prestimulation times coincided with peak induction of HLA-DR and costimulatory B7 molecule (especially CD86) expression on B cells. Finally, addition of CTLA-4/Fc or blocking F(ab′)2 anti-CTLA-4 mAb, plus optimally stimulated non-T cells, to cultures of self-MHC-reactive clones inhibited the induction of TGF-β but not IL-10 or IFN-γ production. In summary, these studies show that activated self-MHC-reactive T cells have the cytokine phenotype of Th3 or T regulatory cell 1 and thus may be important regulatory cells that mediate oral and peripheral tolerance and prevent the development of autoimmunity.

Section: Discussionmentioning

confidence: 63%

Activated Self-MHC-Reactive T Cells Have the Cytokine Phenotype of Th3/T Regulatory Cell 1 T Cells

Kitani

Chua

Nakamura

et al. 2000

108

“…Specifically, Chen et al (17) have shown that CTLA-4 ligation on CD4 ϩ T cells led to the secretion of elevated levels of TGF-␤, and TGF-␤ in turn was shown to be important for the inhibitory activity of CTLA-4 ligation for CD4 ϩ T cell proliferation. However, although a few studies confirmed the observations of Chen et al regarding the importance of TGF-␤ for the inhibitory activity of CTLA-4 ligation for T cell responses (15,16), other studies did not find TGF-␤ to play an important role in the inhibitory activity of CTLA-4 blockade (18,27). Moreover, Sullivan et al (18) A different regulatory cytokine was identified, however, by Schwarz et al (27) as responsible for the inhibitory activity of CTLA-4 ligation for T cell responses.…”

Section: Discussionmentioning

confidence: 66%

Importance of IL-10 for CTLA-4-Mediated Inhibition of Tumor-Eradicating Immunity

Jovasevic

Gorelik

Bluestone

et al. 2004

In this study, we show that engagement of CTLA-4 on tumor-infiltrating lymphocytes from low-dose melphalan (l-phenylalanine mustard (l-PAM))-treated MOPC-315 tumor bearers led to IL-10 secretion. In addition, the inhibitory activity of CTLA-4 ligation for IFN-γ secretion following stimulation with anti-CD3 plus anti-CD28 mAb depended on IL-10 production. Consistent with the importance of IL-10 for CTLA-4-mediated inhibition, administration of neutralizing anti-IL-10 mAb to low-dose l-PAM-treated MOPC-315 tumor bearers (administration of blocking anti-CTLA-4 mAb) resulted in enhanced tumor-infiltrating lymphocyte-mediated anti-MOPC-315 cytotoxicity and led to complete tumor eradication in a higher percentage of mice than that observed with low-dose l-PAM alone. The percentage of MOPC-315 tumor-bearing mice cured following administration of neutralizing anti-IL-10 mAb to low-dose l-PAM-treated MOPC-315 tumor bearers was comparable to that observed following administration of blocking anti-CTLA-4 mAb. Moreover, IL-10 neutralization together with CTLA-4 blockade did not provide added therapeutic benefits to low-dose l-PAM-treated MOPC-315 tumor bearers. Taken together, these results indicate that CTLA-4 blockade improves the therapeutic outcome of low-dose l-PAM for MOPC-315 tumor bearers by inhibiting IL-10 secretion as a consequence of blocking CTLA-4 ligation.

“…Studies using CTLA-4 knockout mice have demonstrated that these mice produce high levels of the Th2 cytokines (IL-4 and IL-5) and, in some cases, show altered responses to ␣CD28 costimulation (24,29,30). In addition, engagement of CTLA-4 in mice suppresses IL-4 production and leads to the development of Th1 cells, while blockade of CTLA-4 polarizes naive cells to a Th2 phenotype (49). Human studies, as well, have shown that Th2 clones express higher percentages of CTLA-4 (50) and that blockade of CTLA-4 in vitro enhances Th2 secretion (28,51).…”

Section: Discussionmentioning

confidence: 99%

CTLA-4 in Filarial Infections: Implications for a Role in Diminished T Cell Reactivity

Steel

Nutman

2003

To determine the role that CTLA-4 might play in mediating the diminished parasite Ag-specific T cell responsiveness that is characteristically seen in filaria-infected patients, several study populations and methods were used. First, quantitative assessment of mRNA expression determined that PBMC from uninfected adolescents exposed in utero to microfilarial (Mf) Ag demonstrated a strong up-regulation of CTLA-4 to the Mf stage of the parasite in contrast to that observed in cells from children born of uninfected mothers (p = 0.005). Next, the frequency of CTLA-4 expression was examined using flow cytometry in cells from filaria-infected and -uninfected individuals ex vivo. Individuals born in filarial endemic regions of the world (with long-standing infections) had greater percentages of CD4+CTLA-4+ cells than did expatriate infected or uninfected individuals (p = 0.005 and 0.05, respectively); in addition, Mf+ patients demonstrated higher frequencies of CD4+CTLA-4+ and CD8+CTLA-4+ cells (p = 0.027 and 0.037, respectively) than did Mf− infected individuals. Of interest, the greatest intensity of CTLA-4 expression occurred in CD4+CD25+ cells, a population purported to include suppressor cells. Finally, in vitro blocking of CTLA-4 expression in PBMC from filaria-infected individuals induced a mean increase of 44% in IL-5 production to Mf Ag, whereas there was a concurrent mean decrease of 42% in IFN-γ production, suggesting that CTLA-4 also acts to alter the Th1/Th2 balance in filaria-infected individuals. Together, these data indicate a significant role for CTLA-4 in regulating the host response to filarial infections and that factors such as length of exposure and patency are important codeterminants.