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EcoSal Plus

Domain 8:


Adaptive Immune Responses during Infection

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • Authors: Lisa A. Cummings1, Brooke L. Deatherage2, and Brad T. Cookson3
  • Editor: Michael S. Donnenberg4
    Affiliations: 1: Department of Laboratory Medicine and Department of Microbiology, University of Washington, Seattle, WA 98195; 2: Department of Laboratory Medicine and Department of Microbiology, University of Washington, Seattle, WA 98195; 3: Department of Laboratory Medicine and Department of Microbiology, University of Washington, Seattle, WA 98195; 4: University of Maryland, School of Medicine, Baltimore, MD
  • Received 21 August 2008 Accepted 17 November 2008 Published 17 September 2009
  • Address correspondence to Brad T. Cookson [email protected]
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  • Abstract:

    The interaction between and its host is complex and dynamic: the host mounts an immune defense against the pathogen, which in turn acts to reduce, evade, or exploit these responses to successfully colonize the host. Although the exact mechanisms mediating protective immunity are poorly understood, it is known that T cells are a critical component of immunity to infection, and a robust T-cell response is required for both clearance of primary infection and resistance to subsequent challenge. B-cell functions, including but not limited to antibody production, are also required for generation of protective immunity. Additionally, interactions among host cells are essential. For example, antigen-presenting cells (including B cells) express cytokines that participate in CD4+ T cell activation and differentiation. Differentiated CD4+ T cells secrete cytokines that have both autocrine and paracrine functions, including recruitment and activation of phagocytes, and stimulation of B cell isotype class switching and affinity maturation. Multiple bacterium-directed mechanisms, including altered antigen expression and bioavailability and interference with antigen-presenting cell activation and function, combine to modify "pathogenic signature" in order to minimize its susceptibility to host immune surveillance. Therefore, a more complete understanding of adaptive immune responses may provide insights into pathogenic bacterial functions. Continued identification of adaptive immune targets will guide rational vaccine development, provide insights into host functions required to resist infection, and correspondingly provide valuable reagents for defining the critical pathogenic capabilities of that contribute to their success in causing acute and chronic infections.

  • Citation: Cummings L, Deatherage B, Cookson B. 2009. Adaptive Immune Responses during Infection, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.11


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The interaction between and its host is complex and dynamic: the host mounts an immune defense against the pathogen, which in turn acts to reduce, evade, or exploit these responses to successfully colonize the host. Although the exact mechanisms mediating protective immunity are poorly understood, it is known that T cells are a critical component of immunity to infection, and a robust T-cell response is required for both clearance of primary infection and resistance to subsequent challenge. B-cell functions, including but not limited to antibody production, are also required for generation of protective immunity. Additionally, interactions among host cells are essential. For example, antigen-presenting cells (including B cells) express cytokines that participate in CD4+ T cell activation and differentiation. Differentiated CD4+ T cells secrete cytokines that have both autocrine and paracrine functions, including recruitment and activation of phagocytes, and stimulation of B cell isotype class switching and affinity maturation. Multiple bacterium-directed mechanisms, including altered antigen expression and bioavailability and interference with antigen-presenting cell activation and function, combine to modify "pathogenic signature" in order to minimize its susceptibility to host immune surveillance. Therefore, a more complete understanding of adaptive immune responses may provide insights into pathogenic bacterial functions. Continued identification of adaptive immune targets will guide rational vaccine development, provide insights into host functions required to resist infection, and correspondingly provide valuable reagents for defining the critical pathogenic capabilities of that contribute to their success in causing acute and chronic infections.

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Image of Figure 1
Figure 1

During infection, there are several points at which pathogen and host immune cells interact. Multiple outcomes for each interaction are possible; the predominant outcome is determined not only by the virulence of the bacterium, but also the innate resistance or susceptibility of the host, and previous exposure of the host to the pathogen (host immune status). Uptake of bacteria by APCs (A) results in either APC elimination by pyroptosis (B) or APC survival (C). Pyroptosis leads to release of the inflammatory cytokines IL-1β and IL-18, and possibly releases bacteria or bacterial Ags for uptake by bystander APCs. Some APCs, such as macrophages, are capable of destroying intracellular bacteria (D). If APCs survive, they may be able to process and present Ag in the context of MHC (E). interferes with this process via multiple mechanisms including repression of Ag expression, bacterial surface modifications that reduce Ag bioavailability and APC stimulation/maturation, and other SPI-2 -dependent processes that mediate bacterial survival within the phagosome (F).

Protected from antibody detection, intracellular can utilize APCs as vehicles for systemic dissemination and replication (G). If APCs are able to overcome bacterial interference to process and present Ag to T cells (E), may still inhibit T-cell activation via stimulation of nitric oxide (NO) production and other direct, suppressive effects (H). Recognition of peptide-MHC on APCs by TCR-expressing naïve T cells leads to activation and expansion of Ag-specific effector T cells (I). Effector CD4+ T cells provide help for the activation of CD8+ CTLs (leading to cytokine production and lysis of infected host cells [J]), and B cells (K). B cells and T cells work synergistically: T cells provide help for antibody production, isotype class switching, and cytokine production by B cells, while B-cell cytokine production supports Th-1 T-cell differentiation, and Ig on B-cell surfaces mediate Ag capture for processing and presentation to T cells (K). Cytokines such as IFN-γ are produced by effector T cells to further enhance APC function and activate bacterial degradation by macrophages (L). In an immune host, previously primed Ag-specific memory T cells (M) may be activated by APCs that process and present Ag (N); activation of these cells and their effector functions (O) is much more rapid than for naïve T cells. In addition, circulating antibodies primed by previous immunization facilitate bacterial uptake via opsonization (P), accelerating the efficiency of Ag presentation up to 1,000-fold. Thus, the ultimate outcome of infection is the cumulative result of complex interactions between pathogen and host.

Citation: Cummings L, Deatherage B, Cookson B. 2009. Adaptive Immune Responses during Infection, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.11
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Image of Figure 2
Figure 2

Interactions with and its host are dynamic and complex. Flagellated and nonflagellated are present in the gut lumen (A), where they must overcome initial barriers including the glycocalyx layer, antimicrobial peptides, and sIgA. cross the epithelium (B) via M cells, by inducing endocytosis in epithelial cells, or following uptake by CX3CR1+ DCs. Bacteria in the gut lumen (A), within epithelial cells (B) and in the PP (C) express FliC protein; interaction of FliC with TLR5 initiates an inflammatory response characterized by production of IL-8 and CCL20 by epithelial cells. Release of inflammatory mediators triggers infiltration of macrophages, neutrophils, and CCR6+ DC. Interaction of these cells with results in at least three possible outcomes: (1) Phagocytosis of bacteria by DC or macrophages, ultimately resulting in inflammatory cell death (flagellin-dependent pyroptosis). Pyroptosis eliminates potential APCs, leads to release of the inflammatory cytokines IL-1β and IL-18, and possibly releases Ags for uptake by bystander APCs (note that flagellin-negative bacteria have a reduced ability to trigger inflammation via TLR5 or pyroptosis).

(2) Uptake of bacteria, which persist within the phagocyte. This interaction can lead to production of NO by APCs (inhibitory for T-cell activation) and upregulation of MHC and costimulatory molecules on DC. In addition, these cells could provide a means of transport to systemic sites such as the liver and spleen. (3) Bacteria are phagocytosed by neutrophils or macrophages and degraded. Mature CCR6+ DC in the PP (C) process and present Ags to naïve T cells; Ags acquired for processing and presentation are restricted to those expressed by bacteria in the gut lumen (A) or PP (C), or Ags that are present in gut lumen, and disassociated from the bacterial soma ([A] MVs, flagellin). Mature DCs that have processed and presented Ag on surface MHC enter into an “activation feedback” loop with naïve T cells: TNF-α and IL-12 produced by DCs enhance activation and expansion of Ag-specific T cells, while IFN-γ secretion by activated T cells further stimulates DC function. Memory T cells primed in the PP (C) express the α4β7-homing receptor as well as CCR6+, predisposing these cells to traffic to the inflamed gut during a secondary infection. Bacteria within APCs disseminate to MLN (D), where Ag presentation to T cells can also occur. Bacteria in the MLN have undergone complete adaptations to the intracellular environment: they no longer express FliC, actively reduce Ag bioavailability, and interfere with APC function (see Fig. 1 ). Dissemination to systemic sites such as liver and spleen (E) follows MLN colonization. Bacteria replicate within APCs at systemic sites. However, in naïve hosts, T-cell responses to Ags expressed by intracellular phase bacteria are generally not sufficient in magnitude or quality, or fail to develop rapidly enough, to combat infection. Further, T cells primed at early stages in the PP (C) will not recognize bacteria growing intracellularly at systemic sites (E), or that fail to express FliC in the PP (C, left).

Citation: Cummings L, Deatherage B, Cookson B. 2009. Adaptive Immune Responses during Infection, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.11
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