CD4+ Cell Development, Function & Dysregulation in Allergy and Autoimmune Diseases

Authors Avatar

CD4+ Cell Development, Function & Dysregulation in Allergy and Autoimmune Diseases

The helper T (TH) cells in the body are central to all branches of the immune system.  They are very aggressive cells, due to their role as ‘molecular guardians of the body’ and so they must be regulated and controlled.  If this regulation or self-tolerance breaks down, then this provides a window for the development of allergy, being a “disease following a response by the immune system to an otherwise innocuous antigen” [12], or autoimmunity, where the body’s immune system targets self antigens.  Before an understanding of the role of different CD4+ cells in immunopathology can be achieved, an appreciation of the different characteristics and interactions of these cells must first be considered.

After preparation of antigen onto a major histocompatibility complex-II (MHC-II), an antigen presenting cell (APC), typically a dendritic cell (DC) or macrophage, will present this to a naive TH cell.  Depending on what type of pathogen has been encountered, the APC will stimulate the polarisation of the naive cell to one subset of TH cells.  This is achieved by the release of specific cytokines from the APC to the TH cell, and the subsets of CD4+ cells are each defined by their unique surface receptors, the cytokines they release and by the types of invaders they target.

The first subset to be discovered was TH1.  These target intracellular pathogens, such as Mycobacterium spp. and mainly utilise phagocytic and cytotoxic cells.  Alongside antigen presentation, interferon- γ (IFN-γ) and interleukin-12 (IL-12) are required from the APC.  IL-12Rβ2, on the CD4+ cell, then induces phosphorylation of the signal transducer and activator of transcription 4 protein (STAT4) and T-bet activation.  The cytokines produced by this cell type, due to STAT4 and T-bet are mostly pro-inflammatory, such as IFN-γ (which up-regulates T-bet thus forming a positive feedback loop), tumour necrosis factor β (TNFβ), IL-2 and lymphotoxin-α (LTα)[1-3].

Around this time, TH2 cells were also discovered in response to extracellular pathogens and parasites e.g. helminths, and these cells induce humoral immunity via immunoglobulin G4 (IgG4) and IgE production.  IL-4 and IL-2 induce this subset, by IL-4R directed phosphorylation of STAT6 which, with GATA-sequence binding protein 3 (GATA3), causes transcription of IL-4.  This is the positive feedback source as IL-4 up-regulates GATA3.  The cytokine profile for this cell includes IL-4 and IL-13 (which induce IgE class switching), IL-5 and Amphiregulin (for eosinophil recruitment) and IL-25 (a self-stimulating cytokine)[1-5].  Note that polymorphisms in GATA3 and IL-4Rα (at position 576. gluarg) have been associated with hypersecretion of IgE from B cells[2].

For reasons that shall be explained later, TH1 cells were associated with inflammatory autoimmunity, and TH2 cells with allergies and asthma.  Very recently, a new subset called TH17 was discovered, which initiated rethinking of the TH1-TH2 mediation hypothesis.  This type of cell is polarised in extracellular bacterial and fungal infections[2,3,6].  Like TH1, this type of cell produces very potent pro-inflammatory cytokines.  TH17 lineage is first induced by low levels of transforming growth factor β (TGFβ), and IL-1β/IL-6.  This up-regulates IL-23R (which is not present on naive CD4+ cells), sensitising the cells to IL-23, and causes cytokine production by RAR-related orphan receptor γt (RORγt) expression.  These include IL-17, IL-17F, IL-21, IL-22 and TNFα.  At this point, IL-21 provides the autocrine positive feedback system, causing proliferation.  IL-21’s importance is highlighted by the condition XSCID, where individuals have no functioning IL-21R.  As B cells have high levels of IL-21R, this results in no humoral responses to infection[7].  To maintain the population of TH17, IL-23 is required, otherwise the cells dissipate[1,2,4,6,8].

Join now!

The final type of CD4+ cell to be considered is the CD4+CD25+ Treg cell, and this is due to the close relationship between TH17 and induced Treg (iTreg) cells.  The main concern of these cells is that of self tolerance, and immunity regulation.  They are induced by the presence of IL-2, high levels of TGFβ but absolutely no proinflammatory cytokine presence.  Instead of TGFβ , all-trans retinoic acid (ATRA) or IL-10 can be used to induce this lineage[9]. It can already be seen that there is a connection with TH17 cells by TGFβ, and because of this RORγt is also expressed in iTregs. ...

This is a preview of the whole essay