1 Department of Dermatology and Allergology, Ludwigs-Maximilians-University, Munich, Germany mroecken@lrz.uni-muenchen.de
2 Institute of Clinical Molecular Biology and Tumor Genetics GSF-National Research Center for Environment and Health, Munich, Germany hueltner@gsf.de
Immunologists are just beginning to understand the early signals required to recruit memory T cells to sites of antigen-specific inflammation. Now it seems that activation of light chain−sensitized mast cells by antigen-specific recognition initiates local immune responses (pages 694−701).
Memory T-cell responses protect the body against pathogens, especially intracellular microorganisms and parasites. T cells become memory T cells in a process called T-cell priming1, which is efficiently carried out by dendritic antigen-presenting cells (DCs). B cells can also prime T cells, but they are much less efficient than the priming powerhouses, DCs, and can in some instances even interfere with priming2,
3 However, an important stimulatory function of B cells has been proposed for the induction of T-cell effector functions in a model of contact hypersensitivity4. Contact hypersensitivity results when T cells overreact to hapten antigens that are frequently in contact with body surfaces.
In a study with implications for contact hypersensitivity and related disorders, Redegeld et al. define a mechanism by which B cells can stimulate T-cell effector function5. This mechanism uncovers a new function for free antigen-specific light chains secreted by B cells. The authors show that light chains sensitize mast cells, which store a variety of biologically active mediators that can be rapidly released upon activation6,
7. Binding of specific antigen to light chain-sensitized mast cells releases mediators and sets in motion an efficient T-cell effector response (Fig. 1).
a, Free light chains are capable of penetrating intercellular spaces where they bind to a 45-kD membrane protein on mast cells. b, Mast-cell degranulation occurs when membrane-bound light chains recognize the corresponding hapten. This reaction initiates T-cell effector functions. TNF and mediators such as T cell−attracting chemokines contribute to T-cell emigration through capillaries. The resulting early edema may pave the way for T-cell emigration in contact hypersensitivity and possibly also autoimmune diseases. Once emigrated, T cells (Th1 and Tc1) start to produce interferon-, the leading effector cytokine of DTHR.
Delayed-type hypersensitivity responses (DTHR) are local immune reactions mediated by tissue infiltrating, interferon-- producing memory T cells that instruct mast cells to cause local inflammation8. DTHR protects against intracellular pathogens, but may also cause harm such as during contact hypersensitivity reactions. DTHR can also cause autoimmune diseases when T cells are directed against autoantigens. Locally, DTHR starts when circulating antigen-specific effector T cells migrate into the tissue harboring the target antigen. But, what makes T cells leave the capillaries?
The early steps of the immune response leading to this migration have been extensively investigated. These include the activation of DCs by innate danger signals, the subsequent DC−T-cell interactions and the polarization and expansion of naive, antigen-specific T cells1,
9. Moreover, T-cell adhesion to capillaries and the chemokine requirement for T-cell migration are well defined10. However, the events telling T cells when and where to leave capillaries for the initiation of local inflammation remain elusive11,
12. Analyses of autoimmune diseases and anti-tumor response have formally proven that T cells need to be guided to their target tissues in order to cause inflammation. A second series of signals is required to induce the adhesion molecules and to create the chemokine gradient responsible for T-cell extravasation from capillaries. Tumor necrosis factor (TNF) can induce the adhesion molecules required for the initiation of DTHR (ref. 13). TNF release can be induced during local infection11, tissue damage or, under experimental conditions, either by X-ray irradiation or by general infection12. But what initiates the extravasation of T cells during the initiation of autoimmune diseases or contact allergy responses?
Surprisingly, immunoglobulin (Ig)-deficient MT-/- mice4 or mast cell−deficient KitW/KitW-v mice8 fail to raise normal DTHR, even though the generation of antigen-specific T cells seems normal in these mice. Thus, neither mast cells nor B cells are needed for T-cell priming but both cell types are indispensible for the effector phase. DTHR are biphasic, with an early peak at 2 hours and a second major reaction after 24 hours or more. Both MT-/- mice and KitW/KitW-v mice fail to develop the early reaction and subsequently generate only very weak DTHR at 24 hours. As mast cells can rapidly release preformed, soluble mediators—including TNF—and reside inside connective tissues6, they have also been thought to act as initiators of DTHR.
Redegeld et al.5 show that antigen-specific light chains, produced in excess by plasma cells, that is, mature Ig-producing B cells, can trigger mast-cell degranulation in vivo and in vitro. The new data also demonstrate that light chains can enter intercellular spaces and bind to a 45-kD membrane protein on mast cells. Importantly, mast-cell degranulation and induction of early edema was found to require exposure of light chain−sensitized mast cells to the specific hapten antigen (Fig. 1). Functional neutralization of light chains inhibited both early edema and DTHR at 24 hours.
The new findings may shed light on other disorders in addition to DTHR. It is possible that peptide-specific light chain−sensitized mast cells might also play a role in the pathogenesis of autoimmune diseases associated with enhanced plasma levels of free light chains, such as multiple sclerosis or rheumatoid arthritis5. The data also raise a series of questions. What is the molecular structure of the putative light chain receptor? Does hapten-recognition by light chain-sensitized mast cells trigger the release of TNF (for induction of adhesion molecules) and of chemokines (for the attraction of T cells)? Does light chain−mediated mast-cell activation cause effects in addition to the capillary leakage and associated edema? What is the role of other potential cellular sources of chemokines such as keratinocytes, DCs or fibroblasts?
In the future, it will be important to define the antigen specificity of light chains associated with autoimmune diseases. Moreover, animal experiments must determine whether specific light chains are involved in T cell−dependent autoimmune diseases such as allergic encephalitis or inflammatory bowel disease. Once these questions are answered, neutralization of light chains may indeed show promise in the therapy of autoimmune diseases. But if the interactions between mast cells and light chains have such an important role in the effector phases of DTHR—as suggested here—the next question arises: What would be the side effects of neutralizing light chains?
Mast cells were long considered to act almost exclusively as effector cells of IgE-dependent allergic reactions. This viewpoint changed dramatically with studies showing that mast cells play a central role in innate immunity and T cell−mediated diseases, including contact hypersensitivity8, psoriasis, rheumatoid arthritis7 and experimental allergic encephalitis (a model for multiple sclerosis)14. If light chains and mast cells have a similar role in initiating autoimmune diseases as for contact hypersensitivity, light chains and mast cells might become new targets in the prevention of relapsing inflammatory autoimmune diseases.
Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature392, 245–252 (1998). | Article | PubMed | ISI | ChemPort |
Fuchs, E.J. & Matzinger, P. B cells turn off virgin but not memory T cells. Science258, 56–59 (1992).
Qin, Z. et al. B cells inhibit induction of T cell-dependent tumor immunity. Nature Med.4, 627–630 (1998). | Article | PubMed | ISI | ChemPort |
Tsuji, R.F. et al. Required early complement activation in contact sensitivity with generation of local C5-dependent chemotactic activity, and late T cell interferon : A possible initiating role of B cells. J. Exp. Med.186, 1015–1026 (1997). | Article | PubMed | ISI | ChemPort |
Wedemeyer, J., Tsai, M. & Galli, S.J. Roles of mast cells and basophils in innate and acquired immunity. Curr. Opin. Immunol.12, 624–631 (2000). | Article | PubMed | ISI | ChemPort |
Stassen, M., Hültner, L. & Schmitt, E. Classical and alternative pathways of mast cell activation. Crit. Rev. Immunol. (in the press).
Biedermann T. et al. Mast cells control neutrophil recruitment during T cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2. J. Exp. Med.192, 1441–1452 (2000). | Article | PubMed | ISI | ChemPort |
Biedermann, T. et al. Interleukin 4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice. Nature Immunol.2, 1054–1060 (2001). | Article | PubMed | ISI | ChemPort |
Kunkel, E.J. & Butcher, E.C. Chemokines and the tissue-specific migration of lymphocytes. Immunity16, 1–4 (2002). | Article | PubMed | ISI | ChemPort |
Ohashi, P.S. et al. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell65, 305–317 (1991). | Article | PubMed | ISI | ChemPort |
Limmer, A. et al. Failure to induce organ-specific autoimmunity by breaking of tolerance: Importance of the microenvironment. Eur. J. Immunol.28, 2395–2406 (1998). | Article | PubMed | ISI | ChemPort |
McHale, J.F. et al. Vascular endothelial cell expression of ICAM-1 and VCAM-1 at the onset of eliciting contact hypersensitivity in mice: Evidence for a dominant role of TNF-. J. Immunol.162, 1648–1655 (1999). | PubMed | ISI | ChemPort |
Secor, V.H. et al. Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J. Exp. Med.191, 813–821 (2000). | Article | PubMed | ISI | ChemPort |
light chain−sensitized mast cells by antigen-specific recognition initiates local immune responses (
light chains secreted by B cells. The authors show that 
, the leading effector cytokine of DTHR.
MT-/- mice
. J. Immunol. 162, 1648–1655 (1999). | 
