IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 13. Regulation of the Immune Response

THE ROLE OF LYMPHOCYTES IN IMMUNOREGULATION

T lymphocytes exert a clearly positive influence on the Immune Response by performing a helper function. Furthermore, depending on the subset of helper T Cells (Th1 or Th2), the immune response can be predominantly humoral or Cell-mediated. There is also compelling evidence that T cells are capable of suppressing the immune response (Fig. 13.8).

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Fig. 13.8. Thymectomized and irradiated mice were reconstituted with Bone Marrow cells, followed 30 days later by the administration of thymocytes and splenocytes together with simultaneous immunization with sheep red Blood Cells (SRBC). On day 44, recipients that received splenocytes from animals primed with an immunogenic dose of SRBC (SRBC-primed splenocytes) mounted an effective immune response (antibody production), whereas in control animals that did not receive splenocytes, the response was moderate. In the group receiving cells from tolerant animals (SRBC-tolerant splenocytes; tolerance was induced with a high dose of SRBC), antibody production was completely absent. This demonstrates that cells from tolerant animals actively suppressed the immune response in the recipients.

CD4⁺ T cells can prevent the onset of autoimmunity

In many experimental autoimmune diseases, CD4⁺ T cells generated following the administration of high doses of autoantigens (often in soluble or disaggregated form) prevent the subsequent Induction of the autoimmune process. For instance, CD4⁺ T cells prevent The formation of autoantibodies against thyroglobulin (Fig. 13.9).

Fig. 13.9. Mice were injected with 20 µg of murine thyroglobulin (Tg) to induce tolerance (control group received no tolerance induction). Half of the tolerant animals were subsequently injected in vivo with depleting anti-CD4 Antibodies to deplete the CD4⁺ T-cell pool. Spleen cells from each of these three groups (non-tolerant mice; tolerant mice; tolerant mice treated with anti-CD4) were transferred to irradiated syngeneic recipients. The recipients were then challenged with murine Tg and LPS, after which anti-Tg antibody production was measured using enzyme-linked immunosorbent assay (ELISA, see Ch. 29). Treatment with anti-CD4 antibodies abrogated The transfer of tolerance.

It has also been established that simultaneous administration of anti-CD4 antibodies (which block antigen presentation mediated by class II MHC molecules) and an immunogenic dose of thyroglobulin to mice not only prevents The Development of autoimmunity, but also induces the generation of a CD4⁺ T-cell population capable of transferring specific tolerance to naive recipient mice (Fig. 13.10). The mechanism by which T cells exert this suppressive effect remains not fully understood. However, recent experiments indicate that the cytokines TGF-$\beta$, IL-4, and IL-10 produced by Th cells can partially or completely suppress the immune response.

Fig. 13.10. Mice immunized with 50 mcg of murine thyroglobulin (Tg) developed thyroiditis and anti-Tg antibodies. Administration of non-eluting anti-CD4 Monoclonal Antibodies for 11 days following immunization, to block the interaction of CD4 with MHC class II molecules, prevented the development of thyroiditis. Transfer of spleen cells from these mice to irradiated recipients prevented the latter from developing thyroiditis upon subsequent Tg immunization. (Immunized mice that received control T cells developed the disease.)

Various subpopulations of Th cells are involved in The regulation of antibody production

Certain observations regarding the regulation of IgE antibody synthesis can be explained by the fact that different subpopulations of CD4⁺ Th cells produce distinct cytokines. There is a cross-regulatory relationship among individual Th cell subpopulations; IFNγ secreted by Th1 cells can inhibit the reactivity of Th2 lymphocytes, whereas IL-10 produced by Th2 cells downregulates the expression of B7 molecules and IL-12 on antigen-presenting cells, which in turn inhibits the activation of Th1 lymphocytes. Furthermore, the expression of the high-affinity IL-12 receptor (IL-12R), required for Th1 cell development, is influenced by the cytokine balance. The high-affinity IL-12R consists of two chains, β1 and β2, both of which are co-expressed only by Th1 cells. The β1 chain is present on both Th1 and Th2 lymphocytes, whereas expression of the β2 chain is induced by IFNγ and inhibited by IL-4. The development of T cell subpopulations is also influenced by IFNα, which favors the generation of Th1 lymphocyte subsets even in the presence of IL-4 and under conditions of IL-12 neutralization. Thus, the preferential activation of Th1 or Th2 cells can lead to immune deviation—the selective development of a specific type of effector response. Such a selective response shift can be exploited in the therapy of autoimmune and allergic diseases.

Resistance and tolerance can be induced by adoptive transfer of CD8⁺ T cells

It has been established that CD8⁺ T cells also regulate the immune response. In the spleens of animals in which tolerance to MBP was induced by oral administration of the antigen (see above), CD8⁴ T lymphocytes were discovered that, upon adoptive transfer, are capable of conferring resistance to EAE in recipients. These T cells not only suppress the T-cell response to MBP invitro, but can also exert a "bystander suppression" effect with respect to other, unrelated Antigens. This effect is presumably mediated by TGFβ.

Regulation of the immune response by CD4⁺ Th2 cells is a normal physiological process

The Role of regulatory effects mediated by CD4⁺ or CD8⁺ T cells under normal physiological conditions remains open to question. However, the normal presence in animals of CD4⁺ T lymphocytes capable of preventing the development of autoimmunity indicates their importance in maintaining normal Homeostasis. Furthermore, it has been demonstrated in rats and mice that depletion of CD4⁺ Th2 cells, which normally produce IL-4 and IL-10, disrupts the regulation of the immune response. This fact strongly proves that the regulation of the immune response carried out by CD4 Th2 lymphocytes (but not CD4⁺ Th1 cells) is a normal physiological process rather than an artifact (Fig. 13.11). According to available data, during the onset of colitis in mice (Fig. 13.11), TGFβ may play a regulatory role in the Development of the pathological process. This is consistent with the results of experiments studying colitis in TGFβ Gene-knockout mice.

Fig. 13.11. This diagram illustrates the incidence of colitis in mice following the transfer of various cell populations. Administration of unfractionated CD4⁺ T cells prevented the development of colitis, whereas the fraction of CD4 cells expressing high levels of CD45RB (CD45RB^hl) induced colitis. Co-administration of anti-IFNγ or anti-TNFα antibodies reduced the incidence of the disease. The cytokine IL-10 (but not IL-4) also influences the onset of colitis in mice. The presented data demonstrate that IFNγ and TNFα cytokines play a role in the Pathogenesis of murine colitis, and that IL-10 can deactivate effector cells. (SCID — severe combined immunodeficiency.)