Mechanism of Immune Responses and Tolerance Induction

The immune system's reaction to antigen depends on (a) the relative frequencies of responding T and B cells and on the thresholds of the binding affinity that their receptors display, (b) the levels of antigen present, and (c) the period during which the antigen remains in secondary lymphoid tissue, where primary immune responses are initiated.

For successful activation of naive T cells, signals derived by antigen-presenting cells (APCs) (Fig. 11.1) are required. The initial signal (Signal 1) is triggered by the antigen displayed on the surface of APCs in the form of peptides bound to histocompatibility molecules that trigger T cells with cognate T-cell receptors, and is

Fig. 11.1 Scheme of T cell activation and targets of immunosuppression drugs. Activation of naïve T cell signals derived by antigen-presenting cell (APC). The initial signal (S1) is triggered by the antigen displayed on the surface of APC in the form of peptides bound to major histocompatibility molecules (MHC) that trigger T cell with cognate T cell receptor (TCR), and is transduced through the CD3 complex. Signal 2 (S2) is derived from ACP's co-stimulation in response to the interaction of CD80 (B7-1) and CD86 (B7.2) with the engagement of CD28 on the surface of T cell. Signals 1 and 2 activate signal transduction pathways that trigger the expression of other molecules, including interleukin-2 (IL-2), CD154, and CD25. Signal 3 (S3) triggers cell via activation of target of rapamycin (TOR) pathway. MMF mycophenolate mofetil, AZA azathioprine, CSP cyclosporine, Tacrolimus (FK506), monoclonal antibodies to CD3 (muromonab), anti-IL2R (basixilimab, daclizumab), anti-CD154 (or CD40L) and CTLA4-Ig (blocking CD28-B7 interaction)

Fig. 11.1 Scheme of T cell activation and targets of immunosuppression drugs. Activation of naïve T cell signals derived by antigen-presenting cell (APC). The initial signal (S1) is triggered by the antigen displayed on the surface of APC in the form of peptides bound to major histocompatibility molecules (MHC) that trigger T cell with cognate T cell receptor (TCR), and is transduced through the CD3 complex. Signal 2 (S2) is derived from ACP's co-stimulation in response to the interaction of CD80 (B7-1) and CD86 (B7.2) with the engagement of CD28 on the surface of T cell. Signals 1 and 2 activate signal transduction pathways that trigger the expression of other molecules, including interleukin-2 (IL-2), CD154, and CD25. Signal 3 (S3) triggers cell via activation of target of rapamycin (TOR) pathway. MMF mycophenolate mofetil, AZA azathioprine, CSP cyclosporine, Tacrolimus (FK506), monoclonal antibodies to CD3 (muromonab), anti-IL2R (basixilimab, daclizumab), anti-CD154 (or CD40L) and CTLA4-Ig (blocking CD28-B7 interaction)

transduced through the CD3 complex. The recognition of antigen by T cell receptors provides specificity to the response. Signal 2 is derived from APC's costimula-tion in response to the interaction of CD80 (B7-1) and CD86 (B7-2) on the surface of dendritic cells (DC), with the engagement of CD28 on the surface of T cells. This is one of the best characterized T cell costimulatory pathways. Signals 1 and 2 activate signal transduction pathways that trigger the expression of others molecules, including interleukin-2 (IL-2), CD154, and CD25. An additional signal (Signal 3) triggers cell proliferation, which is provided by activation of the "target of rapamycin" pathway by IL-12 and IL-15, or by type I interferon. Lymphocyte proliferation also requires nucleotide synthesis. Proliferation and differentiation lead to a large number of effector and memory T cells. When antigens engage with B cells via the B cell receptor, a variety of intracellular signaling pathways are initiated, which ultimately lead to B cell activation and the production of antibodies. Recognition of peptides bound to class I or class II MHC molecules leads to the clonal expansion, activation, and maturation of T lymphocytes, resulting in effector populations of either cytotoxic (CD8+) or helper (CD4+) T cells, respectively. Thus, within days, the immune response generates the agents that recognize tissue damage - activated T cells and antibodies. If only signal 1, but not signals 2/3 are provided, the cell becomes unresponsive to antigen, a state originally called anergy, which can often be overcome by exogenously provided IL-2. Costimulatory blockade may induce anergy and has been successfully applied for peripheral tolerance induction in rodents. The most frequently used agents are anti-CD154 antibody (blocking the CD40-CD154 interaction) and CTLA4-Ig (blocking the CD28-B7 interaction). Peripheral T cell deletion, anergy and regulation are mechanisms of tolerance induction in these models.

Another mechanism of immune tolerance is derived from regulatory T cells (Treg). These cells are well-characterized T cell subsets that play a central role in inducing and maintaining immunologic tolerance (Sakaguchi et al. 2008). One subset of Treg cells is present in 5-10% of unstimulated CD4+ T cells and expresses the IL-2 receptor a-chain (CD25). CD4+ CD25+ Treg cells are generated in the thymus as a functionally mature subpopulation of T cells. However, these cells can also be induced from naive T cells in the periphery as a part of the normal peripheral T cell repertoire where they potently suppress proliferation and cytokine production by both CD4+ and CD8+ T cells (Kang et al. 2007). Naturally occurring Tregs specifically express the transcription factor Foxp3 (forkhead box P3), a member of the forkhead/winged-helix family of transcription factors (Mays and Chen 2007). Foxp3 is a master regulator of Treg development and function. Naive T cells in the periphery can also acquire Foxp3 expression, and consequently Treg function in several experimental settings. T cells are indispensable for controlling unrespon-siveness to self-antigen and suppressing excessive immune responses (Sakaguchi et al. 2008). Notably, evidence for the induction of antigen-specific CD4+CD25+ T regulatory cells by hepatic gene transfer and its importance in maintaining the tolerance to the neoantigen have been demonstrated in in vivo models (Cao et al. 2007b; Mingozzi et al. 2007). These data open a possibility of using gene-based strategy not only for the treatment of diseases, but also for immune tolerance induction.

Skeletal muscle accounts for more than 30% of the human body mass and has important roles in survival of the species. However, little is known about the mechanisms of immunological tolerance to muscle autoantigens. Skeletal muscle fibers do not express MHC molecule I, preventing direct presentation of antigen peptides to self-reactive T cells, although regenerative myogenic cells may express low levels of MHC class I transiently during muscle repair. Therefore, it has been tempting to consider that ignorance is one of the main mechanisms that confer tolerance to this tissue. Ignorance is defined as the lack of antigen detection by the immune system due to absence of presentation, or the lack of appropriate T cell activation conditions. Recent data demonstrated two mechanisms for muscle tolerance (Calbo et al. 2008). The first is ignorance of antigen-specific CD4+ T cells that showed vigorous humoral responses upon antigen-specific immunization. The second was the identification of antigen-specific CD8+ T cells that lost their cytotoxic activity due to upregulation of programmed death 1 (PD-1) that favors tolerance. In this model, there was no evidence that Treg cells participated in muscle immunotoler-ance. However, the potential role of Treg cells in suppressing B and T cell responses was recently demonstrated in a model of gene transfer in skeletal muscle by AAV vectors encoding a highly immunogenic transmembrane transgene (influenza hemagglutinin protein). Adoptive transfer of antigen-specific CD4+CD25+ Treg cells resulted in sustained local transgene expression abolishing cellular toxicity and humoral responses (Gross et al. 2003). Therefore, it is possible that drug-induced and/or cellular therapies aimed at increasing the pool of functional Tregs may prove beneficial in gene therapy for muscular dystrophy.

Modern research into mechanisms of immune tolerance offers the promise of reprogramming the immune system to harness the natural tolerance mechanism of the body. There is growing evidence that pharmacological therapies that induce immune tolerance by diverting the T cell activation pathways augment the apopto-sis rates of activated T cells; or by up-regulating Tregs provide a novel area for the treatment of immune-mediated diseases (Roncarolo and Battaglia 2007; Tao et al. 2007). Thus, preservation of these natural Tregs as well as augmentation of induc-ible subsets may provide an alternative for successful immune modulation, without the side effects of immunosuppressive drugs (Kang et al. 2007).

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