Expansion and activation of CD4(+)CD25(+) regulatory T cells in Heligmosomoides polygyrus infection

Regulatory T cell responses to infectious organisms influence not only immunity and immunopathology, but also responses to bystander antigens. Mice infected with the gastrointestinal nematode parasite Heligmosomoides polygyrus show an early Th2-dominated immune response (days 7-14), but by day 28 a strongly regulatory profile is evident with antigen-specific IL-10 release and elevated frequency of CD4(+) T cells bearing surface TGF-beta. CD4(+)CD25(+) T cells from infected mice show enhanced capacity to block in vitro effector T cell proliferation. CD4(+)CD25(+) cell numbers expand dramatically during infection, with parallel growth of both CD25(+)Foxp3(+) and CD25(+)Foxp3(-) subsets. CTLA-4 and glucocorticoid-induced tolerance-associated receptor, also associated with regulatory T cell function, become more prominent, due to both expanded CD25(+) cell numbers and increased expression among the CD25(-) population. Both intensity and frequency of CD103 expression by CD4(+) T cells rise significantly, with greatest expansion among CD25(+)Foxp3(+) cells. While TGF-beta expression is observed among both CD25(+)Foxp3(+) and CD25(+)Foxp3(-) subsets, it is the latter population which shows higher TGF-beta staining following infection. These data demonstrate in a chronic helminth infection that Foxp3(+) regulatory T cells are stimulated, increasing CD103 expression in particular, but that significant changes occur to other populations including expansion of CD25(+)TGF-beta(+)Foxp3(-) cells, and induction of CTLA-4 on CD25(-) non-regulatory lymphocytes.     

Cover Picture: How many mechanisms do regulatory T cells need? – Eur. J. Immunol. 4/2008

The cover picture has been specifically designed to introduce the first viewpoint series to be published in the European Journal of Immunology. The image combines a picture of a set of scales with a schematic picture of the Treg arsenal, depicting the different cell types influenced by Treg and underlining the crucial role that Treg play in immune regulation. The image is based on a figure in the article by Dario Vignali (pp. 908–911) in which the author discusses the effector functions of Treg and the potential mechanisms involved; this is also the theme of the related article by Cohen et al. (pp.903–907).     

Cover Picture – Eur. J. Immunol. 1/2007

The cover picture, taken from the article by Milling et al. (pp. 87–99), shows a section of the rat small intestine after feeding with E. coli heat labile enterotoxin (Etx). The staining reveals lamina propria DC (CD103^high (red), MCH class II^high (green)); nuclei are counterstained with DAPI (blue). In this article, the authors demonstrate that oral Etx does not increase the number of intestinal DC migrating from the intestine to the mesenteric LN but instead affects activation, antigen transport and localization of the CD172a^high subset.     

Cover Picture – Eur. J. Immunol. 7/2006

The cover has been specifically designed to introduce the 16_th European Congress of Immunology. It combines a picture of the Eiffel Tower with a fluorescence microscopy image of immune cells, underlining the immunological research that will be discussed at the meeting. The immunofluorescence staining shows B lymphocytes (CD45 in red, IgM in blue) forming an immunological synapse with an antigen presenting cell (ICAM‐1 in green) and was kindly provided by Yolanda Carrasco, Cancer Research UK, London.     

Cover Picture: Autoreactive B cells get activated in extrafollicular sites – Eur. J. Immunol. 12/2007

The cover image schematically depicts the mechanisms proposed by Winkler and colleagues (pp. 3330–3333) as underlying the extrafollicular activation of rheumatoid factor B cells by chromatin–immune complexes. The follicular region is shown in orange, the marginal sinus in green, the marginal zone in turquoise, and the red pulp in red. The scheme is based on the data obtained by Shlomchik and colleagues (pp. 3339–3351) in their new mouse model of extrafollicular somatic hypermutation, a characteristic of murine lupus. The model importantly uses IgG anti‐chromatin antibodies rather than conventional immune complexes.     

Early recruitment of natural CD4+Foxp3+ Treg cells by infective larvae determines the outcome of filarial infection

Human helminth infections are synonymous with impaired immune responsiveness indicating suppression of host immunity. Using a permissive murine model of filariasis, Litomosoides sigmodontis infection of inbred mice, we demonstrate rapid recruitment and increased in vivo proliferation of CD4⁺Foxp3⁺ Treg cells upon exposure to infective L3 larvae. Within 7 days post‐infection this resulted in an increased percentage of CD4⁺T cells at the infection site expressing Foxp3. Antibody‐mediated depletion of CD25⁺ cells prior to infection to remove pre‐existing ‘natural’ CD4⁺CD25⁺Foxp3⁺ Treg cells, while not affecting initial larval establishment, significantly reduced the number of adult parasites recovered 60 days post‐infection. Anti‐CD25 pre‐treatment also impaired the fecundity of the surviving female parasites, which had reduced numbers of healthy eggs and microfilaria within their uteri, translating to a reduced level of blood microfilaraemia. Enhanced parasite killing was associated with augmented in vitro production of antigen‐specific IL‐4, IL‐5, IL‐13 and IL‐10. Thus, upon infection filarial larvae rapidly provoke a CD4⁺Foxp3⁺ Treg‐cell response, biasing the initial CD4⁺ T‐cell response towards a regulatory phenotype. These CD4⁺Foxp3⁺ Treg cells are predominantly recruited from the ‘natural’ regulatory pool and act to inhibit protective immunity over the full course of infection.