Cell Co-operation in the Immune Response

In order to infect, the organism must first penetrate the physical barriers of the skin or mucous membranes. After an organism has gained entry, the first line of defence is the non-specific effector mechanisms of the host, in particular the phagocytic cells such as neutrophils. Macrophages also play a role in phagocytosis, but resting macrophages have relatively low levels of phagocytic activity, and require activation through local cytokine release in order to become fully active. In addition to the role of phagocytic cells, some infecting organisms will activate the complement system. Binding of activated complement components to these organisms may act as an opsonin, enhancing phagocytosis of the organism. Activation of complement will also promote local inflammation at the site of infection, through the release of chemoattractant and vasoactive components. In the case of viral infections, infected cells may synthesise interferons and/or be recognised and lysed by natural killer (NK) cells. The non-specific immune mechanisms are particularly important early in infection, as the antigen-specific response takes several days to develop, but the non-specific mechanisms continue to play a role in the immune response right through to resolution of the infection and healing of tissue damage. The importance of non-specific immune mechanisms in infection is emphasised by the susceptibility of individuals who have deficiencies in phagocytosis or in the complement system to various types of infection.

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In addition to triggering these non-specific mechanisms, infection also triggers the antigen-specific adaptive immune response, but this takes several days to develop, due to the need for clonal selection, differentiation and expansion in order to generate antigen-specific effectors. The adaptive immune response to infection involves both the T and B cell mediated compartments of the immune system. The integrity of the adaptive immune system is based on the ability of lymphocytes to recirculate between the blood, somatic tissues and lymphoid tissues. The response can be separated into several distinct phases:

1) The induction phase occurs principally in the lymphoid tissues. Antigen either finds it own way to lymphoid tissues (eg antigen in the circulation passing through the spleen) or it is transported to lymphoid tissues by migratory dendritic cells. Different areas of lymphoid tissues are involved in the induction of different effector arms of the response; most B cell activation occurs within germinal centres, whilst activation of T cells occurs in the T dependent areas (paracortex of lymph nodes or periarteriolar zones of the spleen). In both cases, specialist antigen presenting cells are involved in the initiation of the adaptive immune response - interdigitating follicular dendritic cells in the case of B cell activation, and professional antigen presenting cells - activated macrophages and, particularly, dendritic cells in the case of T cell activation. In addition to the interaction between the antigen receptor and antigen, other signals are required for efficient activation of naive lymphocytes. These additional signals are delivered by receptor: ligand interactions between the lymphocyte and the antigen presenting cell (the cell surface molecules involved in these interactions are called "costimulatory" molecules), and interactions between cytokines and their receptors on the lymphocyte cell surface (see Table 1 of lecture notes on the role of CD4+ T cells in bacterial killing). These requirements for controlling the initiation of the adaptive immune response within the lymphoid tissues regulate its activation, and reduce the chances of uncontrolled or inappropriate immunological activation.

2) Following activation of antigen-specific lymphocytes in the lymphoid tissues, these cells undergo a process of clonal expansion and differentiation. Some of these cells become activated effector lymphocytes (helper T cells, cytotoxic T cells, antibody-secreting plasma cells), whilst other cells remain in a semi-activated and recirculate as memory cells. Memory cells have less stringent requirements for activation on re-contact with antigen in terms of additional signals than naive lymphocytes, and respond more quickly to subsequent exposure to antigen. During the phase of clonal expansion and differentiation, cell cooperation within the immune response plays a major role in determining the outcome of the response. For example (as described earlier in the course) the balance between Th1 and Th2 cells may bias the outcome towards a pro-inflammatory or a pro-allergic type of response.

3) The final phase of activation of the immune response involves the activated effector cells. The different sorts of effector cells, whose roles include the production of antibody by plasma cells, the generation of cytotoxic T lymphocytes and the induction of delayed type hyperrsensitivity reactions and macrophage activation. This stage of the immune response also requires considerable cooperation between different cell types in the immune response, including interactions between antigen-specific and non-specific effector cells, in clearing the infection. As described earlier, the CD4+ T cells play a central role in coordinating the antigen-specific immune response, by providing "help", through cytokine release, for B cells in isotype switching and affinity maturation of antibody responses, for CD8+ T cells in the induction of effector CTL, for enhancement of NK cell function, and for macrophage activation in delayed type hypersensitivity reactions and bacterial and fungal killing.

Ultimately it is left to the non-specific phagocytic cells to clear up the mess, and the macrophages and fibroblasts to resolve any damage caused by the infection and to promote healing. The importance of each component of the immue response in combating infection is demonstrated by the predisposition to infections with particular groups of organisms of individuals with deficiencies in one or more component of the immune response.

Thus, in order to work effectively in response to infections, the different components and cells of the immune system must act cooperatively to eliminate the infecting micro-organism.

© AJC 2007.