BAB 11

Immunological tolerance

Figure 11-1 Fates of lymphocytes after encounter with antigens. In a normal immune response, microbes stimulate the proliferation and differentiation of antigen-specific
lymphocytes. (Microbial antigens are typically recognized by lymphocytes in the presence of costimulators and innate immune responses, which are not shown.) Self
antigens may induce functional unresponsiveness or death of antigen-specific lymphocytes or a change in the specificity of the receptors, making these cells incapable of
responding to the antigen (self-tolerance). Some antigens elicit no response (ignorance), but the lymphocytes are able to respond to subsequent antigen challenge (not
shown). This illustration depicts B lymphocytes; the same general principles apply to T lymphocytes.

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Figure 11-2 Central and peripheral tolerance to self antigens. Immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid
organs and are deleted, change their specificity (B cells only), or (in the case of CD4+ T cells) develop into regulatory lymphocytes (central tolerance). Some self-reactive
lymphocytes may mature and enter peripheral tissues and may be inactivated or deleted by encounter with self antigens in these tissues, or are suppressed by the
regulatory T cells (peripheral tolerance). (Note that T cells recognize antigens presented by antigen-presenting cells, which are not shown.)

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Figure 11-3 Central T cell tolerance. Recognition of self antigens by immature T cells in the thymus may lead to death of the cells (negative selection, or deletion) or the
development of regulatory T cells that enter peripheral tissues.

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Figure 11-4 Induction of T cell tolerance by an aqueous antigen. T cells from transgenic mice expressing an antigen receptor specific for a peptide of ovalbumin are
transferred into normal recipient mice, and the recipients are left untreated or are exposed to the peptide in immunogenic form (with adjuvant) or in tolerogenic form (large
dose of aqueous peptide without adjuvant). A. Lymph nodes of the recipient mice are stained with an antibody that recognizes the ovalbumin-specific T cells. Untreated
(naive) mice contain few of these T cells. In mice given tolerogenic antigen (tolerant), there is some expansion in the number of T cells, but the cells fail to enter the B
cell-rich lymphoid follicles (F). In mice given immunogenic antigen (primed), there is greater expansion of T cells, and these cells do enter the follicles. (From Pape KA,
ER Kearney, A Khoruts, A Mondino, R Mevica, ZM Chen, E Ingulli, J White, JG Johnson, and MK Jenkins. Use of adoptive transfer of T-cell antigen-receptor-transgenic T
cells for the study of T-cell activation in vivo. Immunological Reviews 156:67-78, 1997. Copyright 1997 by Blackwell Publishing.) B. The T cells are recovered from the
transfer recipients and stimulated with ovalbumin peptide in culture, and their proliferative responses are measured by the incorporation of 3H-thymidine into DNA
(expressed as counts per minute per T cell). Naive T cells respond to antigen, cells from primed mice show an increased response, and cells from tolerant mice fail to
respond, an indication of anergy. (From Kearney ER, KA Pape, DY Loh, and MK Jenkins. Visualization of peptide-specific T cell immunity and peripheral tolerance
induction in vivo. Immunity 1:327-339, 1994. Copyright 1994, with permission from Elsevier Science.)

Figure 11-5 T cell tolerance induced by a self antigen in a transgenic mouse model. Two sets of transgenic mice are created, one that expresses a TCR specific for a viral
glycoprotein antigen and another that expresses the antigen in the β cells of pancreatic islets. When these two mice are interbred, in the F1 offspring the T cells
encounter this islet self antigen but do not attack the antigen-expressing islet cells. If the T cells are recovered and challenged with the viral antigen, the cells fail to
respond, indicating that the cells became anergic in vivo. In some similar experiments, the T cells fail to respond in vivo but remain functionally responsive, indicating that
they have ignored the presence of the self antigen. Although the T cells are shown recognizing the antigen directly on islet β cells, it is possible that the antigen is
recognized on dendritic cells in the islets or in draining lymph nodes.

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Figure 11-6 Mechanisms of T cell anergy. T cell responses are induced when the cells recognize an antigen presented by a professional antigen-presenting cell (APC)
and activating receptors on the T cells (such as CD28) recognize costimulators on the APCs (such as B7). If the T cell recognizes a self antigen without costimulation, the
T cell becomes unresponsive to the antigen because of a block in signaling from the TCR complex, or engagement of inhibitory receptors (such as CTLA-4). The
signaling block may be the result of recruitment of phosphatases to the TCR complex, or the activation of ubiquitin ligases that degrade signaling proteins. Regardless of
the mechanism, the T cell remains viable but is unable to respond to the self antigen.

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Figure 11-7 T cell-mediated suppression. Regulatory T cells are generated by self antigen recognition in the thymus (sometimes called "natural" regulatory cells), and
(probably to a lesser extent) by antigen recognition in peripheral lymphoid organs (called "adaptive" regulatory cells). The development and survival of these regulatory T
cells require IL-2 and the transcription factor FoxP3. In peripheral tissues, regulatory T cells suppress the activation and effector functions of other, self-reactive and
potentially pathogenic lymphocytes.

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Figure 11-8 Self antigen-induced death of peripheral T lymphocytes. In response to immunogenic antigens and growth factors, lymphocytes express anti-apoptotic
proteins that promote their survival and allow immune responses to develop (top panel). Self antigens may kill T cells by inducing an excess of pro-apoptotic proteins
(middle panel), or by coexpression of Fas and FasL and engagement of Fas (lower panel).

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Figure 11-9 Central and peripheral tolerance in B cells. Immature B cells that encounter self antigens in the bone marrow die by apoptosis or change the specificity of
their antigen receptors (receptor editing). B cells that encounter self antigens in peripheral tissues become anergic, are excluded from lymphoid follicles, or die by
apoptosis.

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Figure 11-10 B cell tolerance in a transgenic mouse model. A transgenic mouse expressing an Ig specific for the antigen HEL is bred with another transgenic mouse that
produces HEL as a self antigen. In the "double-transgenic" F1 mouse, most B cells express HEL-specific receptors that recognize the self HEL. When immature B cells
recognize the antigen in the bone marrow, the B cells may change their receptors, be deleted by apoptosis, or leave the bone marrow with greatly reduced levels of
receptor expression. Receptor editing is seen only if the Ig transgene is expressed in the normal Ig locus in the genome.

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Figure 11-11 Mechanisms of the decline of normal immune responses (homeostasis). T lymphocytes proliferate and differentiate in response to antigen. As the antigen is
eliminated, many of the activated T cells die by apoptosis. At the end of the immune response, memory cells are the only surviving cells. Although many active regulatory
mechanisms have been suggested as mechanisms for termination of normal immune responses, apoptosis is probably the principal mechanism for the decline of both T
cell and B cell responses (only T cells are shown).

2005 Elsevier