Irmgard FöRster

Controlling Autoreactivity of CD4 T Cells by Local Tolerance Induction

P.  Nieuwenhuis

Introduction to the Proceedings of the 12Th Germinal Centre Conference &#8212; Thirty Years of Germinal Centre Conferences

It is thought that IgA B-cell differentiation is highly dependent on activated CD4+ T cells. In particular, cell-cell interactions in the Peyer&#39;s patches involving CD40 and/or CD80/CD86 have been implicated in germinal-center formation and IgA B-cell development. Also soluble factors, such as IL-4, IL-5, IL-6, and TGF<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B2;</mml:mi></mml:math> may be critical for IgA B-cell differentiation in vivo. Here we report on some paradoxical findings with regard to IgA B-cell differentiation and specific mucosal immune responses that we have recently made using gene knockout mice. More specifically, we have investigated to what extent absence of CD4+ T cells, relevant cytokines, or T-cell-B-cell interactions would influence IgA B-cell differentiation in vivo. Using CD4&#8211; or IL- 4-gene knockout mice or mice made transgenic for CTLA4Ig, we found that, although specific responses were impaired, total IgA production and IgA B-cell differentiation appeared to proceed normally. However, a poor correlation was found between, on the one hand, GC formation and IgA differentiation and, on the other hand, the ability to respond to T-celldependent soluble protein antigens in these mice. Thus, despite the various deficiencies in CD4+ T-cell functions seemingly intact IgA B-cell development was observed.

Eva  G&#228;rdby

Dubrav  Kagrdic

Martin  Kjerrulf

Annakari  Bromander

Michael  Vajdy

Elisabeth  H&#246;rnquist

Nils  Lycke

The Influence of Costimulation and Regulatory Cd4+ T Cells on Intestinal Iga Immune Responses

After intradermal infection of mice with the obligatory intracellular parasite Leishmania major, Langerhans cells (LC) are intimately involved in the induction of the primary T-cell immune response. LC can phagocytose Leishmania and transport ingested parasites from the infected skin to the regional lymph nodes. Since TNF<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math> and IL-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mn>1</mml:mn><mml:mi>&#x03B2;</mml:mi></mml:mrow></mml:math> have been shown to induce LC migration after epicutaneous exposure to skin-sensitizing chemicals, we investigated the involvement of both cytokines in the migration of Leishmania-infected LC. In addition, the relevance of two chemokines of the<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B2;</mml:mi></mml:math> subfamily, macrophage inflammatory protein 1<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math>(MIP-1<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math>) and macrophage chemoattractant protein 1 (MCP-1), was analyzed.In vivo depletion of TNF<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math> significantly reduced the amount of infected LC and the parasite load in the draining lymph nodes. Administration of recombinant TNF<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math> caused the reverse effect. In contrast, the depletion of IL1<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B2;</mml:mi></mml:math> enhanced the parasite-induced LC migration, whereas treatment with recombinant IL-1<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B2;</mml:mi></mml:math>, as well as recombinant MIP- c, reduced the rate of infected LC in the lymph nodes. MCP- did not influence LC migration. Our data demonstrate that TNF<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math> and IL-1<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B2;</mml:mi></mml:math> are regulating the LCmediated transport of Leishmania and also provide evidence for the involvement of macrophage attractant chemokines in this process.

J&#246;rg  Arnoldi

Heidrun  Moll

Langerhans Cell Migration in Murine Cutaneous Leishmaniasis: Regulation by Tumor Necrosis Factor <svg style="vertical-align:-0.1638pt" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FC" d="M545 106q-67 -118 -134 -118q-24 0 -40 37.5t-30 129.5h-2q-47 -72 -103 -119.5t-108 -47.5q-47 0 -76 45.5t-29 119.5q0 113 85 204t174 91q47 0 70 -33.5t43 -119.5h3q32 47 80 140l55 13l10 -9q-47 -80 -138 -201q17 -99 27.5 -136t22.5 -37q23 0 69 61zM333 204&#xA;q-14 98 -31 149.5t-50 51.5q-49 0 -94 -70t-45 -164q0 -55 15.5 -86t40.5 -31q70 0 164 150z" /></g></svg> Interleukin-<svg style="vertical-align:-3.56265pt" height="16.6625" version="1.1" viewBox="0 0 18.1625 16.6625" width="18.1625" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,12.162)"><path id="x31" d="M384 0h-275v27q67 5 81.5 18.5t14.5 68.5v385q0 38 -7.5 47.5t-40.5 10.5l-48 2v24q85 15 178 52v-521q0 -55 14.5 -68.5t82.5 -18.5v-27z" /></g><g transform="matrix(.017,-0,0,-.017,8.222,12.162)"><path id="x1D6FD" d="M558 587q0 -32 -14 -61t-40 -53.5t-48.5 -41t-54.5 -36.5q144 -51 144 -174q0 -55 -43.5 -108t-104.5 -87q-77 -42 -131 -42q-31 0 -54 20t-31 47l11 18q48 -29 108 -29q79 0 119.5 43t40.5 109t-44.5 107.5t-119.5 50.5l22 47q34 1 65 21q96 61 96 157q0 42 -24 67.5&#xA;t-62 25.5q-24 0 -43.5 -9t-35 -29.5t-27 -44t-22.5 -63t-19.5 -75.5t-18.5 -91q-57 -294 -68 -380q-26 -190 -35 -200q-26 -31 -97 -37l-4 26q19 9 48 170l77 413q23 121 52.5 187.5t83.5 114.5q70 62 148 62q51 0 88.5 -34t37.5 -91z" /></g></svg>, and Macrophage Inflammatory Protein-1<svg style="vertical-align:-0.1638pt" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g></svg>

Next to conventional B cells (or B-2 cells), peritoneal B-1 cells have been shown to contribute significantly to the production of IgA-secreting plasma cells in the gut. Evidence for this was mainly based on studies comprising manipulated animals, including lethally X-irradiated and transgenic mice. To examine the ability of peritoneal B-1 cells from untreated mice to switch actively to IgA in vivo, we performed RT-PCR analysis on FACS-sorted peritoneal B-cell subsets from untreated BALB/c mice in order to examine the presence of germline C<mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math> mRNA and mature C<mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math> mRNA transcripts. Germline C<mml:math id="E3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math> and mature C<mml:math id="E4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math> transcripts were readily
detectable in peritoneal B-1 cells (defined as IgMbright/IgDdull), but not, or very little, in peritoneal B-2 cells (defined as IgMdull/IgDbright). Moreover, by subdividing the B-l-cell population in CD5+ B-1a cells and CD5- B-1b cells, it was shown that in vivo expression of germline C<mml:math id="E5" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math> and mature C<mml:math id="E6" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math> transcripts was largely restricted to the B-1b-cell lineage. These results indicate that peritoneal B-1 cells indeed are capable to switch to IgA under normal physiological conditions and hereby further support the view that B-1 cells contribute significantly to the mucosal IgA response, albeit this function appears to be restricted to the B-1b-cell subset.

Rick De Waard

Peter M. Dammers

James W. Tung

Aaron B. Kantor

Jennifer A. Wilshire

Nicolaas A. Bos

Leonore A. Herzenberg

Frans G. M. Kroese

Presence of Germline and Full-Length IgA RNA Transcripts Among Peritoneal B-1 Cells

GALT can be subdivided into several compartments: (a) Peyer's patches (PP); (b) lamina propria
(LP); and (c) intraepithelial leukocyte (IEL) spaces. The B-cell follicles of PP are quiescent in
neonatal and germ-free (GF) adult mice. Germinal centers (GC), including sIgA+ blasts, appear
in the B follicles of formerly GF adult mice about 10-14 days after monoassociation with various
gut commensal bacteria. The GC wax and wane over about a 3-week period, although the
bacterial colonizers remain in the gut at high density. Neonatal mice, born of conventionally
reared (CV), immunocompetent mothers, display GC reactions in PP postweaning, although
pups of SCID mothers display precocious GC reactions at about 14 days of life. Normally, gut
colonization of neonates with segmented filamentous bacteria (SFB) leads to explosive
development of IgA plasmablasts in LP shortly after weaning. Commensal gut bacteria and the
immunocompetency of mothers also appears to control the rate of accumulation of primary B
cells from “virgin” B cells in neonates.Enteric reovirus infection by the oral route can cause the activation of CD8+ T cells in the
interfollicular regions of PP and the appearance of virus-specific precursor cytotoxic T
lymphocytes (pCTL) in the IEL spaces. Such oral stimulation can also lead to “activation” of
both CTL and natural killer (NK) cells in the IEL spaces. More normally, colonization of the gut
with SFB also leads to similar activations of NK cells and “constitutively” cytotoxic T cells.

John J. Cebra

Sangeeta Bhargava Periwal

Gwen Lee

Fan Lee

Khushroo E. Shroff

Development and Maintenance of the Gut-Associated Lymphoid Tissue (Galt): the Roles of Enteric Bacteria
and Viruses

Representing the most potent antigen-presenting cells, dendritic cells (DC) can now be generated from human blood monocytes. We recently presented a novel protocol employing GM-CSF, IL-4, and IFN-<mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> to differentiate monocyte-derived DC in vitro. Here, such cells are characterized in detail. Cells in culture exhibited both dendritic and veiled morphologies, the former being adherent and the latter suspended. Phenotypically, they were CD1a-/dim, CD11a+, CD11b++, CD11c+, CD14dim/-, CD16a-/dim, CD18+, CD32dim/-, CD33+, CD40+, CD45R0+, CD50+, CD54+, CD64-/dim, CD68+, CD71+, CD80dim, CD86+/++, MHC class I++/+++ HLA-DR++/+++
HLA-DP+, and HLA-DQ+. The DC stimulated a strong allogeneic T-cell response, and further evidence for their autologous antigen-specific stimulation is discussed. Although resembling a mature CD 11c+CD45R0+ blood DC subset identified earlier, their differentiation in the presence of the Thl and Th2 cytokines IFN-<mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> and IL-4 indicates that these DC may conform to mature mucosal DC.

Robert Gieseler

Dirk Heise

Afsaneh Soruri

Peter Schwartz

J. Hinrich Peters

In-Vitro Differentiation of Mature Dendritic Cells From Human Blood Monocytes

Intercellular channels called gap junctions enable multicellular organisms to exchange
information rapidly between cells. Though gap junctions are held to be ubiquitous in solid
tissues, we have only recently found them in the lymphoid organs. Functional direct cell-cell
communication has now been confirmed by us and other groups in bone marrow, thymus, and
in secondary lymphoid tissues. What functions do they serve in the lymphoreticular system
where, so far, only cytokines/growth factors and adhesion molecules have been considered as
regulators? Here we show evidence for and refer to published work about functional direct cellcell
communication through gap junctions in germinal center reactions and make proposals for
their role in the immune response.We found a large amount of the connexin43 (Cx43) gap junctions in the germinal centers of
secondary lymphoid follicles. Ultrastructurally and immunohistologically, most of the junctions
were detected on the processes of follicular dendritic cells (FDC) enveloping nondividing
centrocytes in the light zone of germinal centers where B-cell selection is thought to take place.
Further support for this finding came by revealing the Cx43 mRNA in situ at the same location
as the protein. On antigen challenge, gap junctions appeared on the FDC as they formed
meshworks in germinal centers. In order to find out which germinal center cells communicate
directly, we separated FDC-rich, low-density, B-cell fractions from human tonsil. In culture, we
injected single FDC with the low-molecular-weight fluorescent dye, Lucifer Yellow (Mr 457
Da), which passed between adjacent FDC and sometimes from FDC to B cells.Based on these findings and their assigned functions in other tissues, gap junctions may
contribute to germinal center reactions in the following ways: (1) they may regulate follicle
pattern formation by controlling FDC growth, (2) they may be involved in FDC-B-cell signaling
contributing to the final rescue of selected B cells from apoptosis, and (3) they may enable FDC
to work as a functional syncytium providing a cellular internet for integrating germinal center
events. Data supporting these interpretations are briefly discussed.

Tibor Krenacs

Martin Rosendaal

Gap-Junction Communication Pathways in Germinal Center Reactions

The seeding and colonization of the thymus by bone marrow stem cells and the maturation of these cells into mature T lymphocytes are dependent on cell-surface recognition events between different cell lineages within the thymic microenvironment. Positive and negative selection processes within the thymus produce a peripheral T-cell repertoire capable of recognizing peptides derived from foreign antigen bound to self MHC molecules. In addition to the TCR/ MHC-peptide interaction, many other cell-surface molecules act in concert to regulate the
kinetics of cellular interactions and intracellular signaling events during thymopoiesis. We have investigated the complexity of the thymic stroma by using monoclonal antibodies to clone cellmembrane molecules of thymic stromal cells. Thymic-shared antigen-1 (TSA-1) is a molecule of interest because it is expressed by both immature thymocytes and stromal cells. We report herein the structural and evolutionary relationships between TSA-1 and molecules of the Ly-6 superfamily (Ly-6SF), and present evidence that TSA-1 functions as a cell-surface receptor by
binding a cognate cell target molecule on the surface of a subset of thymocytes.

Brendan J. Classon

Richard L. Boyd

Thymic-Shared Antigen-1 (TSA-1)
    A Lymphostromal Cell Membrane Ly-6 Superfamily Molecule with a Putative Role in Cellular Adhesion

The cellular and molecular requirements for β-cell damages in an immune-mediated toxininduced insulin-dependent diabetes mellitus have been studied in the model of multiple low-dose streptozotocin-induced diabetes in rats and mice. It was found that strain-related susceptibility to diabetes induction correlated with a higher level of IL-2, IFN-γ, and TNF-α production, whereas such differences were not observed when IL-1 and NO production by macrophages were analyzed; elimination of immunoregulatory RT6+T cells that increases IFN-γ production, enhances susceptibility to MLD-STZ-induced diabetes; mercury-induced Th-2 cells downregulated
the disease; IFN-γ-mediated macrophage activation to produce proinflammatory cytokines rather than NO is an important event in early diabetogenic effects of invading macrophages; inhibition of IL-1 activity downregulates diabetes induction; and generation of NO in β cells appears to be important for diabetogenic effects. Taken together, data indicate that MLD-STZ diabetes is induced by Th-1 lymphocytes that secrete soluble effector molecules that activate macrophages and promote destruction of β cells possibly by both nitric oxide and nonnitric oxide-mediated mechanisms.

Miodrag L. Lukic

Stanislava Stošic-Grujicic

Allen Shahin

Effector Mechanisms in Low-Dose Streptozotocin-induced Diabetes

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