The Adaptive Immune System

From Horse

Adaptive immunity is a horse's defense system built on specific cellular targeting. It takes time for the immune system to develop its weaponry (up to 96 hours after infection), but ultimately the adaptive response is far more effective because of its precision.

Once infection is identified, antigen is transported to lymphoid organs where it is recognised by naive B and T cells. Clonal expansion and differentiation of these cells occurs, and then the battle begins. The immune system can take several tacks, depending on the type of infection encountered. Ultimately, the goals of the adaptive response are two-fold: to produce neutralising antibody, and to flag up infected cells for destruction. This annihilation can be carried out by the cells of both innate and adaptive immunity.

Actions of the Adaptive Immune System

T-cell receptor binds antigen fragments presented by MHC on the cell surface - B. Catchpole, RVC 2008
B-cell receptor binds two antigens in the ECF - B. Catchpole, RVC 2008

Adaptive immunity is stimulated by the generic actions of innate immunity. Once a foreign organism is identified by the innate immune system, circulating T-cells begin interacting with foreign antigen. Based on their encounter, they can do one of three things: they can kill infected cells directly, they can boost the actions of macrophages to kill infected cells, or they can return to lymph tissue to incite a B cell response. Stimulated B cells will proceed to produce antibody, which can then circulate to fight the infection.

Antigen Recognition

"Antigen" refers to the parts of a foreign organism recognisable by the adaptive immune system. Typically, these are structural proteins, such as the spike proteins of viruses. Antigens can be huge, and are more often identified by epitopes, or smaller fragments of the folded proteins. As such, a single antigen can be recognised by multiple antigen receptors. Antibody has evolved to recognise a dizzying array of antigen epitopes. Antigen can be picked up by lymphocytes in the lymph tissues (T cells and B cells) or the blood stream (T cells only).

T cell receptors (TCR) recognise antigen fragments (that is digestion products) on the surface of cells, whereas B cell receptors (BCR) bind whole antigen in the extracellular fluid. T cells only "see" antigen when it is presented by MHC (Major Histocompatibility Complex) on the cell surface. Antigen digestion and presentation is one of the major functions of the dendritic cells (circulating monocytes) and macrophages. These are referred to as Antigen-Presenting Cells (APCs).

Naive B-cells express IgD and IgM on their cell surfaces, which bind antigen as it is washed into lymph tissue with the afferent lymph fluid. Antigen is presented to B cells by follicular dendritic cells (FDCs), which are also classed as APCs. FDCs can endocytose antigen directly from the afferent lymph or receive them from CD4+ T-cells.

Cellular response: Proliferation and Differentiation

TH1 and 2 selection is influenced by infection - B. Catchpole, RVC 2008
B-cell differentiation - B. Catchpole, RVC 2008
  • T cell response

Once T cells recognise antigen presence in the tissues, they go into action. Their first response is always to recruit help, which is accomplished by returning to the nearest lymph node to carry out clonal expansion. Daughter T cells are created with identical TCRs in order to recognise the identified antigen. These daughter cells are then returned to the circulation via the efferent lymph.

T cells can differentiate three different ways, based on their Cluster of Differentiation (CD) number. All T cells are CD3+, and naive circulating T cells will differentiate upon interaction with antigen to become either CD8+ (cytotoxic) or CD4+ (helper) T cells. CD4+ T-cells will initially become CD4-TH0 cells, and must differentiate to TH1 or TH2 depending on the whim of the adaptive response. TH1 and TH2 cells carry out different types of responses: TH1 is responsible for enhancing the macrophage response, whereas TH2 cells enhance the B cell antibody production. Typically, animals produce a balanced response of TH1 and TH2 cells, though this can lead to pathology, as can a skewed response, depending on the nature of the foreign organism.

  • B cell response

Naive B cells recognise antigen in the lymph tissue when it is presented to them by Follicular Dendritic Cells (FDCs). They also undergo clonal expansion, creating a germinal center in the follicle as they develop and mature into plasma cells. Once mature, plasma cells in the lymph node migrate to the medullary cords and begin secreting antibody into the efferent lymph. Antibody eventually reaches the circulation in order to wage war on the intruder.

Tools of the Adaptive Immune System

Antigen Presenting Cells

  • Macrophages
  • Interdigitating Dendritic Cells
    • Only IDCs can incite a primary response in naive T-cells
  • CD4+ Tcells
  • B-cells

Antigen Binding Molecules

  • Immunoglobulins
  • T-cell Receptor (TCR)
  • Natural Killer (NK) Cells

Adaptive Immunity to Viruses

ADCC, courtesy of Janeway, et al. 2008

Humoral

  • Production of neutralising antibody
  • Antibody-dependent cell mediated cytotoxicity (ADCC)

Antibody-labelled cells can be targeted by NK Cells as another defence against viral infection. Antibody produced against viral protein can attach to infected cells during their budding phase, which effectively labels them for NK targeting. NK cells express Fcγ receptors with which to detect such cells. Once activated, they release a host of enzymes to induce apoptosis of the budding cell.


Cell-Mediated

  • CD8+ T-cell mediated killing of virus infected cells
    • Main cells involved in the immune response to intracellular virus infection
    • Recognition of MHC I-peptide complex
    • Infected cells are killed by apoptosis
      • Perforin and granzymes activate the caspase cascade
      • Fas-ligand triggers the Fas-mediated apoptosis pathway
      • Cytotoxic cytokines (especially TNF-α & TNF-β lymphotoxin) act on TNF receptors to induce programmed cell death

Adaptive Immunity to Bacteria

  • The adaptive and innate responses work together to destroy bacteria
  • The adaptive response ensures the innate response is carried out efficiently

Humoral

  • Complement activation of the classical pathway
    • Production of IgM and IgG makes the complement system more efficient

Cell-Mediated

  • Help for macrophages
    • IgG production (T-helper type II cells and B cells) which improves phagocytosis by opsonisation
    • Infected macrophages are rescued by T-helper type I cells when phagocytosis and digestion mechanisms fail to eliminate the pathogen

Extracellular Infection

  • Complement and phagocytosis
  • B cell and T helper type II cell stimulation
  • Production of IgM which activates the classical cascade
  • Class switching of IgM to IgG which is a good opsonin and targets bacterial Fcγ receptor expressed by macrophages and neutrophils

Vesicular Infection

  • The infected macrophage secretes IL-12
  • IL-12 stimulates T-helper type I cells which release IFN-γ
  • IFN-γ triggers the macrophages to kill the pathogens inside

Adaptive Immunity to Parasites

  • The innate response directs the adaptive response for parasitic infections

Humoral

  • Production of IgE
    • Stimulated by mast cells producing IL-4 (innate response)
    • Isotype switching of B cells to produce |IgE