The Th1 and Th2 subsets of CD4+ T cells induce different types of effector functions that are useful in combating different pathogens. Th1 cells producing Interferon gamma induce cytotoxic, inflammatory responses that are most effective against intracellular parasites, whereas Th2 cells producing IL4 and IL5 induce successful responses against helminth parasites. Although naïve, uncommitted CD4 T cells can differentiate into Th1 or Th2 phenotypes within a few days of initial stimulation, they can also remain uncommitted. These primed, precursor cells (Thpp) produce IL-2 and proliferate rapidly, allowing expansion of antigen-specific cells during an immune response before commitment to a particular effector phenotype. Cells producing only IL-2 also persist for several weeks after immunization, suggesting that these cells may also provide an expanded pool of uncommitted T cells for subsequent immune responses. In common with Treg cells, Thpp express CD73, which can help to generate adenosine that contributes to immune suppression.
In vivo T cell functions are difficult to evaluate, because cytokine secretion phenotypes in addition to Th1, Th2 and Th0 may occur in vivo; and differentiation and selective growth of T cell subsets in vitro can rapidly obscure patterns that occur in vivo. We are using multicolor flow cytometry and Spot assays to detect the simultaneous expression of six or more cytokines by individual human or mouse T cells, to resolve the contributions of partial differentiation, stochastic variation and environmental effects to the spectrum of cytokines produced by individual cells. Short-term cloning experiments are being used to examine the relationship between T cell phenotypes in vivo, versus in long-term tissue culture. These methods are being applied to define the precise T cell phenotypes induced by vaccination and infection by different influenza strains in infants, adults and the elderly.
A Genechip analysis of T cell gene expression revealed that Amphiregulin, an EGF family member, is selectively expressed in activated mouse Th2 cells, and contributes to Th2-mediated elimination of a helminth parasite. This raises the possibility that Th2 cells could contribute to asthma both by enhancing the allergic response and by increasing tissue remodeling. Initial human experiments suggest that regulation of amhipregulin expression is more complex in humans, but still linked to a Type 2 response. A clinical study has been initiated to compare amphiregulin expression in asthmatic patients and controls.