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Manipulation of costimulatory molecules by intracellular pathogens: veni, vidi, vici!!

Khan N, Gowthaman U, Pahari S, Agrewala JN - PLoS Pathog. (2012)

Bottom Line: Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells.Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens.We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.

View Article: PubMed Central - PubMed

Affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India.

ABSTRACT
Some of the most successful pathogens of human, such as Mycobacterium tuberculosis (Mtb), HIV, and Leishmania donovani not only establish chronic infections but also remain a grave global threat. These pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. Costimulatory molecules expressed on the surface of various cells play a decisive role in the initiation and sustenance of immunity. Exploitation of the "code of conduct" of costimulation pathways provides evolutionary incentive to the pathogens and thereby abates the functioning of the immune system. Here we review how Mtb, HIV, Leishmania sp., and other pathogens manipulate costimulatory molecules to establish chronic infection. Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells. This review summarizes the convergent devices that pathogens employ to tune and tame the immune system using costimulatory molecules. Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens. We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.

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Related in: MedlinePlus

Immune response against intracellular pathogens.(A) PRRs of APCs sense pathogens that result in the activation of APCs. (B) This leads to enhanced antigen presentation, upregulation of costimulatory molecules, and secretion of proinflammatory cytokines that promote the activation of T cells. The activated T cells help in elimination of the pathogens. (C) Engagement of costimulatory molecules on APCs by T cells also results in “bidirectional signaling” that activates APCs to restrict the growth of pathogens.
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ppat-1002676-g001: Immune response against intracellular pathogens.(A) PRRs of APCs sense pathogens that result in the activation of APCs. (B) This leads to enhanced antigen presentation, upregulation of costimulatory molecules, and secretion of proinflammatory cytokines that promote the activation of T cells. The activated T cells help in elimination of the pathogens. (C) Engagement of costimulatory molecules on APCs by T cells also results in “bidirectional signaling” that activates APCs to restrict the growth of pathogens.

Mentions: The unilateral “help to T-cell” lymphocentric paradigm of costimulatory pathways has currently evolved into a bilateral signaling model that influences the activity of both T cells and APCs during their interaction (Figure 1) [4], [5]. Costimulatory molecules of CD80/CD28, tumor necrosis factor (TNF)/TNFR, and TIM superfamilies have unmasked the plethora of the possible ligand-receptor interactions that has expanded the understanding of regulation of the immune responses mediated by APCs and T cells. For example, a positive regulator like CD40L (on T cells) when associated with CD40 (on APCs), not only activates T cells but also results in the activation of dendritic cells (DCs); a process that is popularly called “T-cell licensing” [6]. Similarly, ligation of CD28 with CD80 and CD86 is known to induce the secretion of interleukin-6 (IL-6) and interferon-γ (IFN-γ) by DCs and activation, proliferation, and differentiation of B cells [5], [7], [8]. It is reported that 4-1BBL expressed on DCs, binds to 4-1BB on T cells, to bolster DCs help to T cells [9]. Many reports have highlighted the inhibitory roles of CTLA-4 (CD152) and PD-1 (expressed on T cells) with ligands CD80/CD86 and PDL-1/PDL-2 (on APCs), respectively [10], [11]. It clearly suggests that costimulation not only amplifies the magnitude of the activation of T cells and APCs, but fine tunes the immune response as well, thereby controlling the hyperactivation.


Manipulation of costimulatory molecules by intracellular pathogens: veni, vidi, vici!!

Khan N, Gowthaman U, Pahari S, Agrewala JN - PLoS Pathog. (2012)

Immune response against intracellular pathogens.(A) PRRs of APCs sense pathogens that result in the activation of APCs. (B) This leads to enhanced antigen presentation, upregulation of costimulatory molecules, and secretion of proinflammatory cytokines that promote the activation of T cells. The activated T cells help in elimination of the pathogens. (C) Engagement of costimulatory molecules on APCs by T cells also results in “bidirectional signaling” that activates APCs to restrict the growth of pathogens.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375268&req=5

ppat-1002676-g001: Immune response against intracellular pathogens.(A) PRRs of APCs sense pathogens that result in the activation of APCs. (B) This leads to enhanced antigen presentation, upregulation of costimulatory molecules, and secretion of proinflammatory cytokines that promote the activation of T cells. The activated T cells help in elimination of the pathogens. (C) Engagement of costimulatory molecules on APCs by T cells also results in “bidirectional signaling” that activates APCs to restrict the growth of pathogens.
Mentions: The unilateral “help to T-cell” lymphocentric paradigm of costimulatory pathways has currently evolved into a bilateral signaling model that influences the activity of both T cells and APCs during their interaction (Figure 1) [4], [5]. Costimulatory molecules of CD80/CD28, tumor necrosis factor (TNF)/TNFR, and TIM superfamilies have unmasked the plethora of the possible ligand-receptor interactions that has expanded the understanding of regulation of the immune responses mediated by APCs and T cells. For example, a positive regulator like CD40L (on T cells) when associated with CD40 (on APCs), not only activates T cells but also results in the activation of dendritic cells (DCs); a process that is popularly called “T-cell licensing” [6]. Similarly, ligation of CD28 with CD80 and CD86 is known to induce the secretion of interleukin-6 (IL-6) and interferon-γ (IFN-γ) by DCs and activation, proliferation, and differentiation of B cells [5], [7], [8]. It is reported that 4-1BBL expressed on DCs, binds to 4-1BB on T cells, to bolster DCs help to T cells [9]. Many reports have highlighted the inhibitory roles of CTLA-4 (CD152) and PD-1 (expressed on T cells) with ligands CD80/CD86 and PDL-1/PDL-2 (on APCs), respectively [10], [11]. It clearly suggests that costimulation not only amplifies the magnitude of the activation of T cells and APCs, but fine tunes the immune response as well, thereby controlling the hyperactivation.

Bottom Line: Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells.Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens.We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.

View Article: PubMed Central - PubMed

Affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India.

ABSTRACT
Some of the most successful pathogens of human, such as Mycobacterium tuberculosis (Mtb), HIV, and Leishmania donovani not only establish chronic infections but also remain a grave global threat. These pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. Costimulatory molecules expressed on the surface of various cells play a decisive role in the initiation and sustenance of immunity. Exploitation of the "code of conduct" of costimulation pathways provides evolutionary incentive to the pathogens and thereby abates the functioning of the immune system. Here we review how Mtb, HIV, Leishmania sp., and other pathogens manipulate costimulatory molecules to establish chronic infection. Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells. This review summarizes the convergent devices that pathogens employ to tune and tame the immune system using costimulatory molecules. Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens. We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.

Show MeSH
Related in: MedlinePlus