Th2 Cytokine Bias Research Articles

Presence of Activated Antigen-Binding B Cells During Immunization Enhances Relative Levels of IFN-γ in T Cell Responses

AbstractTo examine the influence of Ag presentation by B cells on immune responses, we have used mice transgenic for an Ig heavy chain from a monoclonal anti-azobenzenearsonate (Ars) Ab to deliver Ag to B cells during immunization. A large proportion of transgene-expressing B cells in these mice binds Ars, while transgenic serum Ig shows poor Ars binding. Transgenic B cells present Ars proteins better than their nonhaptenated counterparts. This is associated with an increase in the proliferative responses of transgenic T cells to Ars protein immunization. Although B cell numbers in the transgenic mice are lower, many B cells in them show an activated phenotype, as identified by altered surface levels of peanut agglutinin reactivity, CD23, CD24, CD44, CD62L, and CD86. Even against nonhaptenated immunogens, transgenic responses show significant enhancement in the relative proportions of the Th1 cytokine IFN-γ over the Th2 cytokines IL-4 and IL-10. Haptenated immunogens further enhance the predilection of transgenic mice to produce relatively more IFN-γ. Consistent with this, there is an increase in IgG2a/IgG1 ratios in serum Abs in response to haptenated immunogens in transgenic mice. Adoptive transfer of primed hapten-specific secondary B cells into nontransgenic mice also induces an increase in relative levels of IFN-γ in response to haptenated immunogens. Thus, presentation of immunogen in vivo by activated Ag-binding B cells contributes to enhanced immunogenicity and a Th1 cytokine bias.

The central nervous system environment controls effector CD4+ T cell cytokine profile in experimental allergic encephalomyelitis.

In experimental allergic encephalomyelitis (EAE), CD4+ T cells infiltrate the central nervous system (CNS). We derived CD4+ T cell lines from SJL/J mice that were specific for encephalitogenic myelin basic protein (MBP) peptides and produced both Th1 and Th2 cytokines. These lines transferred EAE to naive mice. Peptide-specific cells re-isolated from the CNS only produced Th1 cytokines, whereas T cells in the lymph nodes produced both Th1 and Th2 cytokines. Mononuclear cells isolated from the CNS, the majority of which were microglia, presented antigen to and stimulated MBP-specific T cell lines in vitro. Although CNS antigen-presenting cells (APC) supported increased production of interferon (IFN)-gamma mRNA by these T cells, there was no increase in the interleukin (IL)-4 signal, whereas splenic APC induced increases in both IFN-gamma and IL-4. mRNA for IL-12 (p40 subunit) was up-regulated in both infiltrating macrophages and resident microglia from mice with EAE. We have thus shown that a Th1 cytokine bias within the CNS can be induced by CNS APC, and that IL-12 is up-regulated in microglial cells within the CNS of mice with EAE. Microglia may therefore control Th1 cytokine responses within the CNS.

IL-4 expression at the onset of islet inflammation predicts nondestructive insulitis in nonobese diabetic mice.

In nonobese diabetic mice, autoimmune diabetes progresses in an age-linked and gender-dependent manner. Insulitis begins in male and female mice at approximately 1 mo of age; however, 70 to 90% of females, but only 10 to 20% of males, become diabetic by 6 mo. Multiple studies propose that proinflammatory Th1 and immunomodulatory Th2 cytokines impact diabetes pathogenesis, but the role of these cytokines in spontaneous diabetes progression is not yet clear. We used quantitative reverse-transcriptase-coupled PCR to analyze expression of cytokines and APC costimulatory molecules in the islets of 20- to 180-day-old male and female nonobese diabetic littermates, and identified three stages in diabetes progression. At 1 to 2 mo of age, islet-infiltrating T cells displayed a Th1 cytokine bias in females, and a Th2 cytokine bias in males. In females, stage II (2-3 mo of age) was characterized by an increase in islet-infiltrating T cells, APC, and Th1 cytokines, whereas male infiltrates did not increase in size, and Th1 cytokine expression continued to decline during this interval. Islet infiltration reached a plateau (stage III) in 3- to 4-mo-old females, months before overt diabetes onset. Our data imply that Th cytokine expression in early insulitis exerts substantial impact on beta cell destruction and overt diabetes. A clinical implication of our results is that young individuals in the early stages of insulitis are ideal candidates for therapeutic intervention to minimize beta cell destruction and morbidity.