Regulation of immune and autoimmune responses by ICOS
Introduction
Our immune system functions to identify and eliminate foreign pathogens. Immune cells are normally tolerant to self tissues; however this self tolerance is lost in autoimmune diseases. Therefore, a fine balance of immune activation and tolerance must be tightly maintained. CD4+ T lymphocytes are essential organizers of most immune and autoimmune responses. They are activated by antigen-presenting cells (APC) such as dendritic cells in the secondary lymphoid organs—lymph node and spleen. After activation, T cells differentiate into either Th1 or Th2 functional subsets, which are specialized in secreting distinct profiles of cytokines to mediate different types of immune responses (Fig. 1) [1], [2]. Th1 cells produce interferon (IFN)γ and TNFα, which mediate inflammatory responses to target cells infected by intracellular bacteria and viruses. In pathological states, Th1 cells are key players in various organ-specific autoimmune diseases, such as type I diabetes, rheumatoid arthritis and multiple sclerosis. Th2 cells, on the other hand, make interleukin (IL)-4, -5, -9, -10 and -13, which together mediate humoral immunity against extracellular pathogens and help to provide protection against intestinal worms. Th2 cytokines also mediate allergic reactions, in part by instructing B lymphocytes to make IgE antibodies.
Th cell activation requires two signals: one through recognition of antigen peptide-MHC complexes by the T cell receptors (TcR) and the second via co-stimulatory receptors binding to their ligands on the same APC. CD28, the most important co-stimulatory receptor, binds to B7.1 (CD80) and B7.2 (CD86) expressed on activated APCs and plays a major role in T cell activation [3]. Studies using T cells derived from CD28-deficient mice demonstrated its role in T-cell proliferation and survival. CTLA4, which binds to CD80 and CD86 with much higher affinity, is induced after T cell activation [4]. CTLA4 plays an inhibitory role in regulating T-cell responses. Mice deficient in CTLA4 displayed polyclonal T cell activationand a lymphoproliferative disorder that results in neonatal lethality. CTLA4 therefore plays a role in down-regulating T cell responses.
In the past several years, the B7 ligand and the corresponding CD28 receptor families have been vastly expanded. The new members of the B7 family are broadly expressed on professional APC and in non-lymphoid tissues, and through their receptors on activated T cells, regulate T cell activation and effector function. PD-1, another ITIM-containing receptor expressed on activated T cells, binds to B7-H1/PDL1 and PDL2/B7DC, both broadly expressed in APC and non-lymphoid tissues [5], [6], [7], [8]. PD-1 plays an important role in maintaining immune tolerance, as PD-1-deficient mice develop multiple autoimmune diseases on different genetic backgrounds [9], [10]. B7-H3 is the newest addition to the B7 family whose receptor has not been identified [11], [12]. B7-H3 was first reported to be expressed by human dendritic cells and to stimulate human T cell proliferation and IFNγ production [11]. We have identified the mouse B7-H3 homologue that is broadlyexpressed in lymphoid and non-lymphoid tissues; a soluble mouse B7-H3-Ig fusion protein binds to activated but not naı̈ve T cells [12]. Recently, we characterized a novel member of the B7 family named as B7 superfamily member 1 (B7S1) [13]. B7S1 is expressed on professional APC and is broadly distributed in non-lymphoid tissues. A soluble B7S1-Ig protein bound to activated but not to naı̈ve T cells. B7S1-Ig reduced T cell proliferation by inhibiting IL-2 production. An anti-B7S1 blocking antibody enhanced T cell proliferation and IL-2 secretion in vitro. In vivo blockade of B7S1 led to enhanced T-dependent immune responses and exacerbation of EAE. Therefore, B7S1 is a novel negative costimulator and regulates the threshold of T cell activation.
ICOS, a third member of the CD28 family, isexpressed on activated but not naı̈ve T cells, and recognizes its own ligand B7h (also named B7RP-1, etc) [14], [15]. B7h is constitutively expressed on certain APC such as B cells and macrophages, and can be induced in non-lymphoid tissues and cells by inflammatory stimuli [15], [16]. Recently, we have generated and analyzed ICOS-deficient mice and indicated ICOS as an important regulator of T cell activation, differentiation and function [17], [18], [19]
Section snippets
ICOS in T cell activation and differentiation in vitro
When human and mouse ICOS were first reported, it was noted that anti-ICOS antibody ligation could enhance human and mouse T cell proliferation and IL-2 production, although not as potently as anti-CD28 stimulation [14], [15]. We have used ICOS-deficient mice to further assess the role of ICOS in T cell activation [17]. Lymph node and splenic cells from ICOS+/+, +/−, and −/− littermates were activated with different doses of plate-bound anti-CD3. ICOS−/− T cells exhibited defective
ICOS regulation of humoral immunity in vivo
To study if the defective activation and cytokine production by ICOS-deficient cells would result in any in vivo immunodeficiency, we immunized wild-type or knockout mice in the footpads and base of the tail with KLH protein using either alum or complete Freud's adjuvant (CFA) as adjuvant. Little IL-4 production was observed by knockout cells from mice immunized with alum or CFA adjuvant, supporting our in vitro analysis described above. Consistent with this, knockout mice from both
Negative regulation of EAE by ICOS
B7H is expressed in non-lymphoid tissues as well as B cells. Most interestingly, its expression is greatly induced in some tissues by the pro-inflammatory cytokine TNFα. With this in mind, we examined the importance of ICOS in an inflammatory autoimmune disease. Experimental autoimmune encephalomyelitis (EAE) can be induced in C57BL/6 mice by injection of myelin oligodendrocyte glycoprotein (MOG) peptide 35–55 in CFA [23], [24]. When we used ICOS+/+ mice with the C57BL/6×129 F2 genetic
An essential role of ICOS in CIA
To determine whether ICOS plays a role in pathogenesis of autoimmune diseases, we backcrossed ICOS knockout mice on to DBA/1 background and analyzed the role of ICOS in CIA [25]. These ICOS+/+ and ICOS−/− mice were immunized with type II chicken collagen II (CII) protein emulsified in CFA at the base of tail followed by two boosts. ICOS+/+ mice uniformly developed severe joint inflammation (Fig. 2a). But the ICOS−/− mice did not. By visual inspection, they appeared grossly identical as
Conclusion and future perspectives
Using ICOS−/− mice, we have begun to define the important function of the ICOS-B7h pathway in immune regulation and in pathogenesis of autoimmune diseases. Unlike CD28, which is essential for T cell activation and function, ICOS appears to function by fine-tuning effector T cell differentiation and function. ICOS is not required for the global T cell activation or Th1/Th2 differentiation; instead, it is required for production of certain key effector cytokines (IL-4 and IL-17, for instance).
Acknowledgements
We thank our many collaborators for scientific contribution, Caroline Bishop for critical reading of the manuscript, and the entire Dong Lab for discussion and help. Our work is supported in part by grants from National Institute of Health. C. Dong is a recipient of an Arthritis Investigator award from Arthritis Foundation.
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