Page 406 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 26 Host Defenses to Intracellular Bacteria 387

such as IL-6; and of the chemokines CXCL1, CXCL8, and CXCL6, are rapid producers of IL-17 at sites of bacterial implantation.
which attract neutrophilic and eosinophilic granulocytes and Transient participation of γδ T cells in protection and a unique
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prolong their survival. Th17 cells, too, have limited importance requirement for γδ T cells in granuloma formation have been
for protection in murine models against primary infection with described for murine listeriosis and TB. Murine γδ T cells appear
mycobacteria, salmonellae, and listeriae. However, Th17 cells to recognize peptides presented by nonpolymorphic MHC class
can drive more rapid Th1 responses against pulmonary TB in I molecules, whereas human γδ T cells respond to nonpeptidic
mice after vaccination, resulting in enhanced protection. IL-17 phosphorylated metabolites, notably from the isoprenoid pathway
is also required for optimally protective Th1 responses during of bacterial and host origin. 43
murine F. tularensis infection. 39 MAIT cells are primarily localized at mucosal sites, and current
Despite the convenience of defining T-cell populations in evidence suggests that they play a role in control of bacterial
terms of subsets, recent evidence suggests considerable plasticity infections in mucosal tissues, such as lung (M. tuberculosis) and
in cytokine production by T cells. This was first suggested by gut (gram-negative bacteria) tissues. Antigenic ligands include
demonstration that all subsets could produce IL-10, which derivatives of vitamin B 2 (riboflavin), produced by many intracel-
regulates potency of T-cell responses to limit host collateral lular bacteria, including salmonellae and mycobacteria. 44-46
damage during immune responses. IL-10 expression might be CD1 comprises a group of nonpolymorphic MHC-related
an intrinsic control mechanism common to all T cells. However, molecules that can present glycolipid antigens to unconventional
reduction in T-cell potency also favors chronic intracellular T cells. In humans, group 1 CD1-restricted T cells respond to a
bacterial infection. T-cell subsets may acquire the ability to variety of microbial glycolipids, including LAM, PIMs, mycolic
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produce additional cytokines by expression of additional tran- acids, sulfatides, sulfoglycolipids, and lipopeptides. Group I
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scription factors or by remodeling chromatin structure. Future CD1 molecules are absent in mice. The group II CD1 molecule
research will redefine T-cell behavior during intracellular bacterial CD1d is present in both humans and mice and controls develop-
infection. ment of natural killer T cells (NKT cells) that express the NK
cell marker NK1.1. Upon antigen activation, these T cells rapidly
CD8 T Cells produce cytokines and are capable of producing both IL-4 and
Infection of mice deficient in specific T-cell subsets has conclu- IFN-γ. Bacterial antigens recognized by NKT cells, PIMs from
sively demonstrated a role for CD8 T cells during listeriosis and mycobacteria, and glycosphingolipids from Ehrlichia and Sphin-
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TB. Furthermore, CD8 effector T cells have been identified in gomonas spp. have been identified. NKT cells also respond to
granulomas of patients with tuberculoid leprosy with low numbers host endogenous lysosomal lipids loaded onto CD1d. 48
of bacteria. The cytolytic potential of these T cells can serve two In summary, unconventional T cells often recognize nonpep-
roles in infection with intracellular bacteria, namely, target cell tidic ligands of bacterial origin, emphasizing that they play a
killing or lysis of cells that are unable to control the infection, particular role in immunity against bacteria, including intracel-
thus releasing the bacteria for phagocytosis by more activated lular bacteria. Because of the highly skewed T cell receptor, these
cells. In humans, CD8 T cell–mediated killing is cell contact T cells are specific for a limited variety of bacterial ligands. Because
dependent and based on production of perforin, granzymes, of their less demanding antigen recognition and activation
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and granulysin. Finally, CD8 T cells are also a potent source requirements, unconventional T cells may fill a gap between
of IFN-γ and TNF-α, thus contributing to direct activation of prompt innate resistance and the delayed conventional T-cell
infected macrophages to enhance protective mechanisms (see response.
Fig. 26.3).
CD8 T cells recognize antigenic peptides in the context of T-Cell Memory and Regulation of Immune Responses
MHC class I gene products, which are responsible for presentation Long-term protective immunity against infectious agents relies
of antigens residing in the cytosol. Initially, therefore, it was on immune memory, which forms the basis for the success of
mysterious how CD8 T cells were stimulated by intracellular all vaccines. Memory T cells can be divided into central memory
bacteria, which were thought to have a uniquely restricted T (T CM ) cells and effector memory T (T EM ) cells, based on dif-
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phagosomal residence. However, with the knowledge that many ferential surface phenotypic and tissue migration patterns.
intracellular bacteria egress into the cytoplasm, one major T EM cells accumulate in peripheral tissues where they express
mechanism for MHC class I processing became obvious: proteins effector functions, whereas T CM cells persist in lymph nodes,
secreted by bacteria in the cytoplasm undergo antigen processing where they rapidly develop into T EM cells after secondary antigen
and presentation similarly to newly synthesized proteins of viral encounter. The tissue-resident memory T (T RM ) cells are local-
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or host origin. Yet, alternative contact points for MHC class I ized to mucosal sites, where they provide efficient protection
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molecules and bacterial peptides exist. Cross-presentation by against invading pathogens. Although it is generally accepted
noninfected antigen-presenting cells (APCs) of antigens engulfed that memory T cells can survive in the absence of persistent
within apoptotic blebs from infected cells represents a critical antigen, little is known about the induction and maintenance of
pathway to induce CD8 T cells by phagosomal bacteria (see long-lasting T-cell memory in chronic infections with intracellular
below). One major advantage of CD8 T cells over CD4 T cells bacteria. 51
is their recognition of antigen bound by MHC class I gene
products, which are expressed by almost all host cells. Thus CD8 B Cells
T cells recognize professional and nonprofessional phagocytes Although antibodies produced by B cells appear to play a minor
equally well. biological role in infections with intracellular bacteria, many
facultative intracellular bacteria spend some time outside their
Unconventional T Cells host cells, where they are accessible to antibodies. Thus antibod-
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The relevance of the γδ T cells to antibacterial immunity is ies contribute to protection against salmonellae. Besides antibody
incompletely understood. Several studies indicate that γδ T cells production, B cells are potent APCs for soluble antigens, including