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Fighting tumors
A number of mechanisms by which a malignant cell can escape immune surveillance have been proposed. One of these, "immune deviation", proposes that the tumor environment may skew the immune response from a therapeutic to a nontherapeutic response. Studies in tumor models have correlated Th1 polarization with a therapeutic response, whereas Th2 responses have been shown to be less therapeutic. Jensen et al. (p. 2014 ) examined the concept of immune deviation by studying regression of the mammary adenocarcinoma cell line 4T1 in Stat6-/- mice. Since Stat6-/- mice are deficient in Th2 cells due to decreased IL-4 production, T cells in these mice will be polarized to the Th1 type. The authors found that tumor-bearing Stat6-/- mice contained a population of T cells primed by the Stat6531–539 peptide, and that these mice were much more resistant to 4T1 growth than wild-type mice. The Stat6531–539-reactive T cells were effective in eliminating 4T1 tumor cells in adoptive transfer studies. In addition, when the authors transferred bone marrow cells from Stat6-/- mice to wild-type mice, followed by tumor challenge, they found that these mice were as susceptible to 4T1 as were wild-type mice. These findings indicate that rejection of the 4T1 tumor cells is dependent on the anti-tumor primed Stat6531–539-reactive T cells and is not due to a skewing to a Th1 response.
Analyzing adjuvant action
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in vitro, and an increase in serum IL-12 was observed when mice were injected with pertussis toxin-treated dendritic cells. Pertussis toxin was shown to mediate its effect on dendritic cells via extracellular signal-regulated kinase (ERK). When ERK signaling was inhibited, maturation of pertussis toxin-treated dendritic cells was decreased and the ability of these cells to induce T cell IFN-
production and experimental autoimmune uveitis was blocked. The adjuvant effects of pertussis toxin in inducing experimental autoimmune uveitis can therefore be mediated via dendritic cells. For whom the Toll sounds
Mast cells are involved not only in allergic and inflammatory reactions but also in the host’s response to bacterial infection. Mast cells are located in areas strategic to host defense; they are found in high concentrations just below epithelial surfaces, including those of the skin and gastrointestinal and respiratory tracts. Upon activation, mast cells release a number of preformed and newly synthesized mediators including histamine, lipid mediators, chemokines, and cytokines, thereby initiating a local inflammatory response. On p. 1625
, McCurdy et al. report on the expression of Toll-like receptors (TLR) in human cord blood-derived mast cells and the effects of different TLR ligands on mast cell mediator release. They found that human mast cells express TLR1, TLR2, and TLR6 mRNA, but not mRNA for TLR4. This differs from murine mast cells, which express both TLR2 and TLR4. Interestingly, the authors showed that different TLR2 ligands effect different functional responses in mast cells. Bacterial peptidoglycan and yeast zymosan, signaling via a TLR2/TLR6 heterodimer, elicit release of GM-CSF, IL-1
, and cysteinyl leukotriene, but not degranulation. In contrast, a synthetic lipopeptide that signals through a TLR2/TLR1 complex causes considerable degranulation but has little effect on release of GM-CSF, IL-1, and cysteinyl leukotriene. These distinct responses may be important in directing the outcome of an infection.
Big-hearted mice
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Location, location, location!
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-deficient T cells to examine the relationship between T cell activation, clonal expansion, and effector differentiation. They found that naive T cells stimulated via the TCR and CD28 in the absence of Th1 or Th2 polarizing cytokines exhibited growth arrest in an immature state. Arrested T cells retained the ability to develop into Th1 or Th2 cells after secondary TCR/CD28 activation under either Th1 or Th2 promoting conditions. However, arrested T cells restimulated with TCR/CD28 in the absence of Th1- or Th2-polarizing cytokines appeared anergic. This block could be overcome by masking CTLA-4, although cytokine production remained dependent upon the appropriate cytokine receptor-mediated signals. Naive cells activated in the presence of CTLA-4/Ig bypassed the arrested phenotype, even in the absence of cytokine-mediated signals. The data suggest that CTLA-4 maintains an anergic checkpoint that can be overcome by Stat4- and Stat6-transduced cytokine signals. This could ensure that effector differentiation occurs only in an appropriate cytokine milieu. Toward a more avid T cell
An increase in the avidity of CD8+ T cells, without any change in TCR affinity, has been shown both during the primary response as well as between the primary and recall responses. Bullock et al. (p. 1822 ) immunized mice with peptide-coated dendritic cells to study the impact of Ag density on the number and avidity of primary, memory, and recall CD8+ T cells in vivo. Using dendritic cells with a range of different MHC/peptide complex densities, the authors showed that increasing epitope density increased the size of the primary response without evidence for altered avidities of the CD8+ T cells. However, during memory expansion and in recall responses, a trend to higher avidities was observed as the Ag density on the dendritic cells increased, whereas the magnitude of the responses was largely unaffected. Therefore, it appears that Ag dose during boosting is more crucial than is epitope density during the primary response in determining high avidities during recall responses.
Toxoplasma compartmentalized
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as well as via perforin-mediated lysis of infected cells. Kwok et al. (p. 1949
) analyzed the compartmentalization and stage-specificity of Ag on the induction of a parasite-specific CD8+ T cell response in mice. The investigators expressed the model -galactosidase Ag in both secreted and cytoplasmic forms under the control of a promoter used only in the tachyzoite stage, or as a secreted Ag under the control of a promoter used only in the bradyzoite stage. They found that only -galactosidase-secreting tachyzoites induced a primary CD8+ T cell response, which declined in the spleen but persisted in the brains of mice with chronic Toxoplasma encephalitis. In mice previously primed with -galactosidase-secreting tachyzoites, infection with either tachyzoites or bradyzoites secreting -galactosidase induced a transient -galactosidase-specific CD8+ T cell response in the brain. Understanding the compartmentalization and stage-specificity of T. gondii Ag may be important in the development of vaccines using this organism. EAE induction and prevention
Experimental autoimmune encephalomyelitis (EAE) is an animal model used to study the autoimmune disease multiple sclerosis. Two papers in this issue used EAE models to look at mechanisms involved in the development of this disease. In the first, Jones et al. (p. 1690 ) examined the role of epitope spreading in disease progression. A number of reports have shown a correlation between epitope spreading, where the repertoire of T cells specific for myelin epitopes becomes more diverse, and disease progression. However, a substantial body of evidence also exists against a need for epitope spreading in progression of the disease. Using mice with only a single TCR specific for the myelin epitope BP 1-11, the authors showed that disease progression, including remissions and relapses, occurred in the absence of epitope spreading. In the second report, Lobell et al. (p. 1806 ) present data showing that vaccination of Lewis rats with DNA encoding a peptide of myelin oligodendrocyte glycoprotein (MOG) was protective against MOG-peptide-induced EAE. This work follows previous reports that vaccination with DNA constructs encoding two other EAE encephalitogens (a peptide of myelin basic protein or a proteolipid protein peptide) was protective in subsequent induction of EAE with the same peptide. The presence of Th1-promoting CpG motifs in the plasmid backbone were required for protection against EAE induction with the MOG-peptide. Hence DNA vaccination can protect against EAE induced by the three main encephalitogens involved in the pathogenesis of multiple sclerosis.
Summaries written by Kaylene J. Kenyon, Ph.D.
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