Alpha and lambda interferon together mediate suppression of CD4 T cells induced by respiratory syncytial virus.

The mechanism by which respiratory syncytial virus (RSV) suppresses T-cell proliferation to itself and other antigens is poorly understood. We used monocyte-derived dendritic cells (MDDC) and CD4 T cells and measured [(3)H]thymidine incorporation to determine the factors responsible for RSV-induced T-cell suppression. These two cell types were sufficient for RSV-induced suppression of T-cell proliferation in response to cytomegalovirus or Staphylococcus enterotoxin B. Suppressive activity was transferable with supernatants from RSV-infected MDDC and was not due to transfer of live virus or RSV F (fusion) protein. Supernatants from RSV-infected MDDC, but not MDDC exposed to UV-killed RSV or mock conditions, contained alpha interferon (IFN-alpha; median, 43 pg/ml) and IFN-lambda (approximately 1 to 20 ng/ml). Neutralization of IFN-alpha with monoclonal antibody (MAb) against one of its receptor chains, IFNAR2, or of IFN-lambda with MAb against either of its receptor chains, IFN-lambdaR1 (interleukin 28R [IL-28R]) or IL-10R2, had a modest effect. In contrast, blocking the two receptors together markedly reduced or completely blocked the RSV-induced suppression of CD4 T-cell proliferation. Defining the mechanism of RSV-induced suppression may guide vaccine design and provide insight into previously uncharacterized human T-cell responses and activities of interferons.

Human T cell cytokine responses are dependent on multidrug resistance protein-1.

Multidrug resistance protein-1 (MRP1) belongs to subfamily C of the ATP-binding cassette transporters, and exports leukotriene C(4) and organic anions including the fluorescent calcium indicator indo-1. The observation that leukocytes from patients with an autoimmune disease exported indo-1 at a higher rate than controls prompted the hypothesis that MRP1 contributes to the function of activated cells. To test this, we defined the expression of MRP1 on resting and activated human T cells, and determined whether T cell activation is dependent upon MRP1 function. MRP1 is expressed on resting memory but not on naive CD4 and CD8 T cells. After activation through the TCR, cord blood CD4 T cells express high levels of MRP1. Blockade of MRP1 with the specific inhibitor MK-571 abrogated superantigen-induced expression of IFN-gamma, tumor necrosis factor-alpha, IL-10, IL-2, IL-4 and CD69 by T cells without affecting their viability, and was reversible upon removal of MK-571 from the culture media. Electrophoretic mobility shift assays demonstrate that MRP1 blockade with MK-571 induces activation of the transcriptional repressor peroxisome proliferator-activated receptor-gamma in CD4 T cells, thus providing insight into the potential mechanism by which their responses are abrogated.

CXCR3 is induced early on the pathway of CD4+ T cell differentiation and bridges central and peripheral functions.

Chemokine receptors on T cells are frequently categorized as functioning either in immune system homeostasis within lymphoid organs, or in peripheral inflammation. CXCR3 is in the latter category and is reported to be expressed selectively on Th1 cells. We found that CXCR3 was expressed in vivo on newly activated tonsillar CD4(+) T cells. Using CD4(+) T cells from cord blood, we found that CXCR3 was induced by cellular activation in vitro independently of the cytokine milieu, although on resting cells, expression was maintained preferentially on those that had been activated in type 1 conditions. In inflamed tonsils, CXCR3(+)CD4(+) T cells were localized around and within germinal centers. The inference that CXCR3 has a role in germinal center reactions was supported by the finding that the CXCR3 ligand CXC chemokine ligand 9 was expressed in a pattern demarcating a subset of germinal centers both in tonsil and in lymph nodes from an HIV-infected individual. We next investigated the role of CXCR3 on peripheral effector/memory CD4(+) T cells by comparing its pattern of expression with that of CCR5, another Th1-cell associated chemokine receptor. Analysis of cells directly from peripheral blood and after activation in vitro suggested that CXCR3 expression preceded that of CCR5, supporting a model of sequential induction of chemokine receptors during CD4(+) T cell differentiation. Taken together, our data show that CXCR3 can be expressed at all stages of CD4(+) T cell activation and differentiation, bridging central function in lymphoid organs and effector function in peripheral tissues.