Adaptive acquired specific immune response

In many situations, the non-specific immune responses described above (e.g. phagocytosis, NK cell activation, inflammation), with which we are born and that occur in the first few hours of infection, may be sufficient to overcome the pathogens. If not, disease can ensue and the body may recover after the activation of adaptive immune responses against the invading pathogens (see Figure 7.1). There are two types of adaptive immune responses, namely antibody-mediated immune (AMI) responses and cell-mediated immune (CMI) responses.

The most relevant cells in providing adaptive immune responses are lymphocytes, which make up between 25 and 35% of white blood cells; their total number in a healthy individual is close to one billion (1012). Two major types of lymphocytes, called B cells and T cells, are present in the blood in a 1:5 ratio. B cells develop into mature immunocompetent cells in the red bone marrow and each B cell expresses an antigen receptor (i.e. antibody) of a single specificity on its cell surface and is responsible for the AMI response (see Figure 7.2). In AMI, the binding of antigen to antigen receptor (i.e. antibody) on B cells can result in the activation and differentiation of B cells into antibody-secreting plasma cells. However, to ensure full activation and differentiation of B cells into plasma cells in response to most antigens and antibody class switching (e.g. from low-affinity IgM subclass into high-affinity IgG subclass) requires a co-stimulator signal provided by the interaction of B cells with CD4+ Th cells (i.e. T cells expressing CD4 antigen - see below). The binding of CD154 molecules on the CD4+ T cell to CD40 molecules on the B cell, together with production of cytokines such as IL-4 and IL-5 by CD4-Th cells, can result in the full activation of B cells and their differentiation into antibody-producing plasma cells (see Figure 7.2).

Each plasma cell secretes up to 2000 antibodies per second against the original antigen and this process can continue for about 4-5 days. The antibody production by plasma cells can be increased by the cytokine IL-6. The secreted antibodies then circulate in the blood and lymphatic system, and bind to the original antigens, marking them for elimination by several mechanisms including: activation of the complement system, promotion of phagocytosis via opsonization, and mediation of ADCC with effector cells such as macrophages, NK cells and neutrophils (see Figure 7.2).

In contrast to the AMI response, a CMI response against the invading pathogen is mediated by T cells. Whereas B cells complete their maturation in the bone marrow, T lymphocytes develop from pre-T cells in the bone marrow and mature in the thymus into CD4+- or CD8+-expressing T cells (see Figure 7.2). In CMI, CD8+ T cells recognizing the target antigen proliferate and differentiate into CD8+ cyto-toxic T cells (Tc) which kill the target antigens by delivering a lethal dose of the cytokines lymphotoxin and perforin or by directing apoptosis (see Figure 7.2). In contrast, T cells expressing CD4 antigen are called T-helper cells (Th0) and the binding of antigens to such cells results in their proliferation and differentiation into two CD4+ Th cell subsets, Th1 and Th2. Th1 cells produce cytokines such as IL-2 and IFNy which stimulate CMI responses against intracel-lular pathogens and tumour cells. In contrast, Th2 cells produce the cytokines IL-4, IL-5 and IL-6, which play a central role in regulating the AMI response against extracellular antigens and pathogens (see Figure 7.2). In addition, the production of cytokines by Th1 cells can enhance phagocytosis of the target antigen by macrophages of the innate immune system (see Figure 7.2). For this reason, CD4+ helper T cells are viewed as the backbone of the immune system and their crucial role has been highlighted in patients with AIDS where the Th cells are targeted by the virus (Altfeld and Rosenberg, 2000). In a normal uninfected individual, the number of CD4+ T cells is between 800 and 1200 cells/m3 of blood. When the number of CD4+ T cells falls below 200/mm3 of blood towards the final stage of HIV infection, such individuals become particularly susceptible to opportunistic infections, caused by microbes that usually do not cause disease in healthy individuals, as well as cancers such as Kaposi's sarcoma and lymphomas. Indeed, AIDS is part of the evidence that supports the idea that immunosuppression can increase the incidence of cancer and the immune surveillance concept (Scadden, 2003; see below).

In addition to CD8+ cytotoxic and CD4+ Th cells, there are other populations of T lymphocytes that inhibit the immune response by releasing inhibitor cytokines; these cells are called suppressor T cells (Ts) (McHugh and Shevach, 2002).

MHC molecules, antigen recognition and processing in cellmediated immunity

As described above, T lymphocytes are responsible for CMI responses against foreign antigens and the aim of most cancer vaccines under investigation or in development is to create antigen-specific, T-cell-mediated immune responses against tumour antigens.

However, as with B cells, successful activation of different T cells requires the presence of two signals, namely a recognition and a co-stimulatory signal. The first signal is recognition of the antigen by the antigen receptors on the surface of T cells, called T-cell receptors (TCRs), which results in the movement of the T cells from a resting phase of the cell cycle (i.e. G0) to G1 phase. However, unlike some B cells which can bind directly to an antigen with their unique antigen receptors (i.e. antibodies), the TCRs on both CD4+ and CD8+ T cells can recognize only a fragment of an antigen that has been processed and presented in association with a unique cell surface self-antigen called the major histocompatibility complex (MHC) antigen. There are two major types of self-MHC molecules which are also called human leukocyte antigens (HLAs). MHC class I molecules are found on all body cells except red blood cells and present the intracellular antigens to the TCRs on CD8+ T cells. In contrast, MHC class II molecules are present only on the surface of antigen-presenting cells (APCs), such as macrophages, B lymphocytes and dendritic cells, and are important in the presentation of exogenous antigens to the TCRs on CD4+ Th cells (Figure 7.3).

After the binding of the MHC-antigen fragment complex to the TCR, the T cells become activated only if they receive a second signal called a co-stimulatory signal. This second signal has been shown to be essential for full activation of T cells. Most co-stimulatory molecules are cell adhesion molecules that allow the two cells to adhere to one another for a longer period and result in sustained proliferation and differentiation of T cells (Figure 7.3), e.g. activation and differentiation of CD4+ T cells into Th cells requires the binding of CD28 molecules on CD4+ T cells to CD80/CD86 molecules present on APCs. This in turn results in the production of IL-2, IL-2 receptor expression, and cell cycle progression and proliferation of activated T cells. In contrast to CD4+ Th cells, the full activation of cytotoxic T cells against the target cells is promoted by the binding of the CD2 molecule on CD8+ T cells to the CD58 molecule on target cells and by the interaction of lymphocyte functional antigen 1 (LFA-1) on the T cell with the intercellular adhesion molecule 1 (ICAM-1) on the target cells. Recognition of the antigens by the antigen receptors on the lymphocyte, in the absence of co-stimulatory signals, results in the production of no cytokines, a state of immunological unresponsiveness called anergy, or even increased apoptosis (Frauwirth and Thompson, 2002). Indeed, deficiencies or abnormality in some of these components can help tumour cells to escape recognition and destruction by T cells (see below).

Co-stimulatory molecules

Activated CD4+ T cells (Th) secrete cytokines that amplify both CMI and AMI (e.g. IL-2 and IL-4). Some remain as long-lived memory Th cells

Co-stimulatory molecules

Degradation of intracellular antigen

Tumour cell, APC or a cell infected by viruses

Degradation of intracellular antigen

Tumour cell, APC or a cell infected by viruses

Class II Processed CD8+ T cell MHC antigen receptor

Figure 7.3 Successful activation of antigen-specific T-cell responses requires two signals: (a) CD4+ T-helper cells are activated only when the T-cell receptor (TCR) recognizes an antigen fragment, from exogenous antigens, in association with MHC-II molecules (signal 1) and receives a co-stimulatory signal by binding the CD28 molecule on T cells to a CD80/CD86 molecule on the antigen-presenting cell (signal 2). (b) CD8+ T cells are activated only when the TCR recognizes an antigen fragment, from endogenous antigens, in association with MHC-I molecule (signal 1) and receives a co-stimulatory signal via interaction between other cell surface (adhesions) molecules (signal 2). Recognition without the second signal results in anergy (i.e. a prolonged state of inactivity) and programmed cell death (apoptosis).

Class II Processed CD8+ T cell MHC antigen receptor

Activated CD8+ T cells proliferate and differentiate into cytotoxic T cells (Tc) and kill target cells by inducing apoptosis or by delivering a lethal dose of lymphotoxin and perforin.

Some remain as long-lived memory Tc cells

Figure 7.3 Successful activation of antigen-specific T-cell responses requires two signals: (a) CD4+ T-helper cells are activated only when the T-cell receptor (TCR) recognizes an antigen fragment, from exogenous antigens, in association with MHC-II molecules (signal 1) and receives a co-stimulatory signal by binding the CD28 molecule on T cells to a CD80/CD86 molecule on the antigen-presenting cell (signal 2). (b) CD8+ T cells are activated only when the TCR recognizes an antigen fragment, from endogenous antigens, in association with MHC-I molecule (signal 1) and receives a co-stimulatory signal via interaction between other cell surface (adhesions) molecules (signal 2). Recognition without the second signal results in anergy (i.e. a prolonged state of inactivity) and programmed cell death (apoptosis).

Adaptive immune system, immunological memory and immunization

Two characteristic features of the adaptive immune response are specificity for a particular antigen and immunological memory. Once the invading pathogens are destroyed by the adaptive immune response, some of the activated B and T lymphocytes differentiate into thousands of memory B and T cells. When the body encounters the same pathogen for a second time, these memory cells, which can remain in circulation for decades after the first exposure, increase their population so rapidly that the pathogens are destroyed before the individual develops any signs of disease (Sprent, 2003).

Indeed, the development of memory B and memory T cells against the antigen on the infectious agent or cancer cell is the rationale for successful immunization. The immunization of children against infectious agents is estimated to save the lives of 3 million children a year by helping the body to prevent primary infection (Andre, 2003). However, the development of vaccines against cancer is more challenging because, unlike vaccines against infectious diseases, cancer vaccines are developed for the treatment of disease that is already present in the body and not merely for its prevention (Berd, 1998; Moingeon, 2001).

In summary, the full activation of the immune system and successful destruction of any foreign antigens, cells and infectious agents by adaptive immune responses requires cooperation of immune cells of adaptive and innate immunity, the production of cytokines by such cells and the presence of co-stimulatory signals, which are essential for activation and proliferation of antigen specific B and T cells. Any abnormalities in one of the above components can lead to a state of immunological unresponsiveness against the target antigen.

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment