Immunity to Infections

Abstract

Understanding how different pathogens are sensed and recognised by the immune system and an appropriate response generated is critical for devising control strategies. Innate immunity is deployed immediately after the infection, while it takes several days before adaptive immunity effectively kicks in. Key differentiating features of two types of responses are specific recognition and the formation of immunological memory during adaptive immunity. Both types of immune responses are interdependent and play critical role during defence against infections. Recently, emerging trends that challenge well‐established paradigm how innate and adaptive immunity are defined and categorised are highlighted. In addition, factors that make some pathogens less amenable to immune control and unresolved issues in infection immunity are discussed.

Key Concepts

  • A concerted activity of innate and adaptive immune mechanisms is critical for defence against microbes.
  • Innate immune responses are not so specific while adaptive immune responses exhibit specificity effected by TCRs and BCRs expressed by T and B cells respectively.
  • Some mediators however act at the interface of innate and adaptive immunity.
  • The outcome of infection depends on several host and pathogen properties.
  • Although most infectious agents utilise strategy to outmanoeuvre immunity but immune evasion is not absolute.
  • Most chronic infections induce upregulation of inhibitory receptors on T cells a phenomenon commonly known as immune exhaustion.
  • Blocking signalling induced by inhibitory receptors can reverse function in exhausted T cells.
  • Immune modulatory strategies could be useful to achieve optimal protection conferred by prophylactic and therapeutic vaccines.

Keywords: infections; innate and adaptive immunity; cytokines and interferons; differentiation of T and B cells; memory cells; host and pathogen properties and outcome of disease; microbiome and disease susceptibility

Figure 1. Types of immune defences against microbes: Three types of defence mechanisms provide antimicrobial immunity. The first line of defence comprises of mechanical and chemical barriers such as intact skin, mucosal surfaces laden with mucocilliary expulsion system and antimicrobials. Second line of defence includes innate immune responses that comprise of both humoural and cellular components. The humoural components are complement proteins, defensins, lysozymes in various secretions, and cellular components consist of innate immune cells such as neutrophils, basophils, eosinophils, macrophages, dendritic cells, NK (natural killer) cells and so on. The third line of defence also includes both humoural (antibodies) and cellular components (T and B cells). NK cells, NKT cells and γδ T cells may be categorised to be working at the interface of innate and adaptive immune responses. Innate and adaptive immune mechanisms cross‐regulate each other as is shown by forward and reverse arrows. There is a sequential deployment of each of the defence mechanism to fend off any pathogenic insults.
Figure 2. Different immune cells that are involved in antimicrobial immunity. Hematopoietic stem cells in bone marrow give rise to myeloid stem cells and lymphoid stem cells. Myeloid stem cells further give rise to granulocytes such as neutrophils, eosinophils, basophils, mast cells and monocytes. Monocytes when migrating to different tissues further differentiate into macrophages and dendritic cells. The later cells are responsible for presenting antigens to T cells to activate them. Lymphoid stem cells give rise to T, B and NK cells. T and B cells predominantly serve as cellular components of adaptive immunity. B cells can recognise antigens in their native form to further differentiate into plasma cells, which make antibody molecules. Some activated B cells further differentiate into memory B cells. T cells recognise antigen‐processed antigens presented in association with MHC (major histocompatibility complex) molecules. In order to activate CD8+ T cells, peptides derived from microbes are predominantly processed through proteasomal pathway to generate peptides that are loaded onto MHC class I molecules. Exogenous antigens are taken up by professional antigen‐presenting cells (APCs) such as macrophages and dendritic cells to be predominantly processed by phagolysosomal pathway. Peptides thus presented are loaded onto class II MHC molecule to stimulate CD4+ T cells. However, peptide generated from exogenous antigens can also be loaded onto class I MHC molecules and activate CD8+ T cells. This process is called antigen cross‐presentation and is one of the pathways involved in activating antiviral CD8+ T cells especially against herpes and pox viruses.
Figure 3. Activation of JAK/STAT pathways by interferon signalling in target cells to confer antiviral immunity. The binding of type I IFN (interferon) to receptors induces dimerisation of the receptor. This leads to the activation of already bound Janus kinase (JAK). Kinases (K) autophosphorylate the receptor to create docking sites for signal transducer and activator of transcription (STAT) protein (S) binding. Upon binding to the receptor STAT molecules are tyrosine phosphorylated by the activity of JAKs, the STATs then form active dimers that translocate into the nucleus to regulate transcription and translation of many genes including those required for the degradation of mRNA (messenger ribonucleic acid) and inhibition of protein translation. This creates an antiviral state in the cell.
Figure 4. CD4+ T cells help during differentiation of B cells. During a germinal centre reaction, B cells take up antigens through their BCR (B cell receptor) in order to process them into peptides that are presented preferentially onto class II MHC expressed by B cells. B cells engage specific CD4+ T cells and activate them. Activated CD4+ T cells produce cytokines to help B cells in their activation and class switching to form different isotypes of antibodies. The cells that produce antibodies are called plasma cells. In the process, memory B cells that have undergone somatic hypermutation and affinity maturation are also produced.
Figure 5. Differentiation of CD4+ T cells during infections. APCs take up exogenous antigens and process them to present in context with class II MHC molecules to antigen‐specific CD4+ T cells. This serves as signal I during the activation process. Costimulatory molecules such as B7.1 and B7.2 are upregulated by APCs as a result of signalling through their innate immune receptors and PAMPs interaction. Costimulatory molecules serve as signal II during activation of CD4+ T cells, which ligate CD28 expressed on CD4+ T cells. Depending on the initial burst of cytokines produced in the microenvironment, CD4+ T cells differentiate into one of the many phenotypes such as Th1, Th2, Th17, TFH or Tregs. The differentiating cytokines are IL‐2 and IFN‐γ (for Th1), IL‐4 and IL‐6 (for Th2), IL‐6 and TGF‐β (for Th17), IL‐6, IL‐1β and TNF‐α (for TFH) and IL‐2 and TGF‐β (for Tregs). Each of these cell type has predominant roles in conferring protection against intracellular pathogens (Th1), parasites (Th2), bacteria and fungi (Th17). TFH are predominantly involved in helping B cells activation and differentiation so that different classes of antibodies are produced while Th1 cells are mainly involved in helping CD8+ T cells for their activation.
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Sehrawat, Sharvan, and Rouse, Barry T(Jun 2017) Immunity to Infections. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000478.pub3]