Costimulation and coinhibition are physiologically related to polyclonal activation and inhibition

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The immune system did not develop in isolation, but in response to various infecting agents with which it had to deal. As discussed above, infecting agents possess polyclonally active agents that stimulate or inhibit immune responses. However, many infecting agents stimulate inappropriate responses, and others do not induce the appropriate reponses. The immune system adjusts partly to this situation by making use of internal activators and inhibitors. Classical polyclonal activation may synergize with or antagonize antigen-specific immune responses. The endogenous functional counterparts of such activation and inacti-vation in the immune system are costimulation and coinhibition, both of which are mediated by polyclonally distributed receptors and ligands.


Synergistic interactions between a clonally restricted antigen receptor and a polyclonal receptor form the basis of costimulation. This is a physiologic process in which receptor-ligand interactions occur, allowing different types of cells to communicate with each other. T cells are activated by signals transmitted via the antigen receptor and other signals transmitted via a second receptor or class of receptors. The classical costimulator of T cells is the receptor CD28 whose ligand is B7 (CD80/86), but there are many others. B cells are activated by signals transmitted via the antigen receptor and other signals transmitted via a second receptor or class of receptors. The classical costimulatory receptor for B cells is CD40 whose ligand is CD40L which is found on T cells. CD40L also acts as a receptor for T cell signaling, so that a given cell surface element can serve as both receptor and ligand. Other costimulatory receptor-ligand systems have been defined, and evidence suggests others (as yet not characterized). It has been suggested that spontaneous autoimmune disease is due to an overabundance of costimulatory signals.


Interactions between a clonally restricted antigen receptor and a polyclonal receptor can result in co-inhibition. Because lymphocytes must be removed when they are not needed or, indeed, are dangerously autoimmune, they possess receptor-ligand pairs that result in lymphocyte death. The expression of these pairs is increased upon lymphocyte activation. In T cells, ligation of the antigen receptor and CTLA-4 leads to inactivation of the T cell. If, however, CD28

is also ligated, the result is pronounced T cell activation. Therefore, the outcome of contact with antigen via the antigen receptor is influenced greatly by what other connections the T cell makes. Mice that lack CTLA-4 develop a lethal autoimmune disease by one month of age.

B cells also have a defined coinhibitor system, the low avidity Fc receptor called Fey RUB which binds the Fc portion of secreted antibody that is attached to antigen receptors. Antibody is able to suppress immunoglobulin production and to inactivate B cells. This inhibition requires the Fc portion of antibody and involves a coligation of the antigen receptor with the Fc receptor. This coligation results in phosphorylation of the Fc receptor, attachment of a phosphatase (SHP-1), and inactivation of the B cell. A strain of autoimmune mice lacks SHP-1, while mice lacking the Fc receptor have increased immune responses but are not noticeably autoimmune. CD22, another B cell coinhibitory receptor that signals via the recruitment of SHP-1, may take over the function of the Fc receptor when it has been deleted.

Defects in other coinhibitory mechanisms are associated with autoimmunity. Apoptosis defects result from the lack of the receptor Fas (lymphopro-liferative, or lpr trait) or the lack of the Fas ligand (generalized lymphadenopathy, or gld trait). Excess of elements (e.g. Bcl-2) that prevent lymphocyte death or apoptosis also result in autoimmunity. All of these defects are associated with polyclonal activation followed by the emergence of specific antiself responses and clinical autoimmunity. Spontaneous clinical autoimmunity has been associated more with the lack of coinhibition than with augmented costimulation.

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How To Bolster Your Immune System

How To Bolster Your Immune System

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