Fundamentals of bovine immunity

A robust immune system is essential for optimal cattle performance, as it helps combat health challenges like pathogens, injuries, and stress. The high demands of the cattle industry, however, can strain immune function, leading to increased vulnerability in both cows and calves. Understanding the mechanisms and functions of the immune system is fundamental for effective herd management.

There are two immunity pathways: the innate or nonspecific immunity, and the adaptive or specific immunity. Upon pathogen invasion, the innate immune system responds first, aiming to prevent infection and activate the adaptive immune response. This nonspecific mechanism is rapid, acting within minutes to hours, whereas the adaptive response takes longer, typically days to weeks, to develop (figure 1).

Prefer to listen to this article? Click the play button below and enjoy our podcast!

Innate immunity

The first line of defence against most microorganisms consists of physical and functional barriers such as skin and mucosal surfaces. When these barriers are compromised, a natural immune response is activated, designed to prevent infection, eliminate invading pathogens, and stimulate the acquired immune response. The innate immune response is not antigen-specific and has no immunologic memory; meaning it cannot recognize the same pathogen upon subsequent exposure.

The innate immune system components include:

Effector cells

• Granular leukocytes, of which neutrophils and eosinophils are phagocytes:
  • Neutrophils are the first immune cells to be activated, and their primary function is the phagocytosis and destruction of invading microorganisms.
  • Eosinophils have similar phagocytic and metabolic functions to those of neutrophils but are especially effective against parasitic infections.
• Mononuclear phagocytes:
  • Monocytes are produced in the bone marrow and differentiate into macrophages and dendritic cells in the tissues.  
  • Macrophages kill bacteria that are resistant to neutrophils activity and act as antigen-presenting cells (APCs) by ingesting, processing, and presenting antigens to lymphocytes to stimulate cell-mediated and humoral immune responses.
  • Dendritic cells (DC) are specialized antigen-presenting cells and, together with macrophages, initiate adaptive immune responses
• Natural killer (NK) cells: rapidly activated within 1–2 days post-infection, NK cells are a critical component of the innate defence response, both by directly killing infected cells and by cytokine-mediated activation of the cell-mediated adaptive immune response.
• Innate lymphoid cells: these cells mediate immune response and regulate tissue homeostasis and inflammation.
• Endothelial/epithelial cells: they recognize the microorganisms and produce different cytokines.

Antimicrobial peptides

Defensins create a chemical barrier that limits infections at epithelial surfaces by directly attacking invading bacteria. 

Soluble mediators

Cytokines, small protein or glycoprotein molecules secreted by cells, are crucial for the modulation of the innate immune response. Local effector cells of the innate immune system are activated by inflammatory cytokines such as type I interferons (IFN-α/β) and proinflammatory cytokines such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α). They release additional cytokines and chemokines that attract neutrophils and monocytes to the affected area. These recruited cells further signal to attract DC cells, NK cells, T cells, and B cells. In contrast, cytokines like IL-4, IL-10, and IL-17 actively promote the resolution of the inflammatory response, helping to control and conclude the immune cascade. Cytokines also play a crucial role in the adaptative immune response (see below).

Cellular receptors

Toll-like receptors (TLRs) are a key component of innate immunity. Binding of TLRs to pathogens´ receptors activates several mechanisms of innate immunity and helps initiate the acquired immune response. 

Adaptative immunity

When innate immunity fails to eliminate infectious agents, the adaptive immune system is activated. Following the initial exposure to an antigen, an optimal response typically develops within 2 to 3 weeks. Adaptive immune responses are highly specific to the inducing pathogen and can provide long-lasting protection.

The primary functions of the adaptive immune response include:

• Recognizing specific "non-self" antigens and distinguishing them from "self" antigens.
• Generating pathogen-specific immunologic pathways that target and eliminate specific pathogens or infected cells.
• Developing immunologic memory that enables a rapid response to subsequent infections by the same pathogen.
  

The cells of the adaptative immune system include:

T cells

T cells derive from hematopoietic stem cells in the bone marrow and, following migration, mature in the thymus in the fetus and the juvenile. In mature individuals, development of new T cells in the thymus slows down and T-cell numbers are maintained through division of mature T cells outside of the central lymphoid organs. They express a series of unique antigen-binding receptors on their membrane, known as the T-cell receptor (TCR), and have the capacity to rapidly proliferate and differentiate with the appropriate signals. 

T cells require the action of APCs, which express a group of proteins known as the major histocompatibility complex (MHC). MHC are classified as either class I, which presents intracellular peptides, or class II, which presents extracellular peptides to T cells. 

T cells are activated when they encounter an APC that displays antigens bound to its MHC molecules. The MHC-antigen complex activates the TCR, and the T cell secretes cytokines which further control the immune response. This antigen presentation process stimulates T cells to differentiate primarily into:

• CD8+ cytotoxic T cells (CTLs), which are primarily involved in the destruction of cells infected by foreign agents, such as viruses. They are activated by the interaction of their TCR with peptide bound to MHC class I molecules, producing effector cells that induce apoptosis of target cells. After the infection is resolved, most effector cells undergo apoptosis and are cleared by phagocytes, although some of them persist as memory cells, which can rapidly differentiate into effector cells upon subsequent exposure to the same antigen.
• CD4+ T helper (Th) cells, which are activated when their TCR recognizes antigens bound to class II MHC molecules. Upon activation, Th cells release cytokines that modulate the activity of various immune cell types:
  • Th1 response is characterized by the production of interferon-gamma (IFN-γ), which activates macrophages' bactericidal functions and enhances antiviral immunity. Th1-derived cytokines also promote B cell differentiation, leading to the production of opsonizing antibodies that improve phagocytosis.
  • Th2 response is marked by the release of cytokines such as IL-4, IL-5, and IL-13, which stimulate the development of immunoglobulin E (IgE) antibody-producing B cells. Th2 cells also promote the recruitment of mast cells and eosinophils, essential for effective responses against parasites. Additionally, they enhance the production of specific IgG subclasses that help combat bacterial infections.
    

Most Th cells will die upon resolution of infection, with a few remaining as Th memory cells. A subset of CD4+ T cells known as regulatory T cells (Treg) helps limit and suppress immune activity to prevent inappropriate reactions to self-antigens and the development of autoimmune diseases.

B cells

Cytokines 

Lymphocyte activation, growth, and differentiation are regulated by cytokines. 

• IL-2 stimulates T and B cells proliferation and activates NK lymphocytes, increasing their cytotoxic activity.
• IL-4 plays a crucial role in the response to some parasites.
• IL-12 activates NK lymphocytes and induces CD4+ cells to differentiate.
• IFN-g activates macrophages, neutrophils, and NK cells.
• TNF-a acts synergistically with IFN-γ to activate phagocytic cells.
• TGF-b regulates inflammatory processes. 

Antibody-mediated immunity

Humoral or antibody-mediated immunity is primarily driven by B-cell production of antibodies, which contain viral proliferation during the acute phase of infection. The B cell's antigen-binding receptor recognizes specific antigens and binds to them. Local Th cells then secrete cytokines that promote B cell proliferation and influence the type of antibodies produced. The secreted antibodies bind to antigens on the surfaces of pathogens, marking them for destruction through complement activation, enhancing phagocytosis via opsonization, and facilitating elimination by immune effector cells. Once the pathogen is cleared, the antigen–antibody complexes are removed through the complement cascade.

Five major types of antibodies are produced by B cells. 

• IgM accounts for approximately 5–10 % of the total Ig in serum and colostrum in bovine. It is the first antibody built during an immune response and is very effective in neutralizing pathogens in the early stages of a disease. Elevated levels can be a sign of recent infection or exposure to antigen (figure 2).
• IgG is the predominant class of antibody in the serum and colostrum. It is produced in a delayed response to an infection and can be retained in the body for a long time, which makes it the most useful for passive immunization. The detection of IgG usually indicates a prior infection or vaccination.
• IgA is the major mucosal antibody.
• IgE plays a role in the immune response against parasites.
• IgD, whose function is poorly understood and has been demonstrated in cattle relatively recently. 

Once an infection is established, cell-mediated immune mechanisms are highly important in host defence against most intracellular pathogens.

Cell-mediated immunity

Cellular immunity is mediated by T lymphocytes which defend against most viruses and those organisms that infiltrate into cells where antibodies and complement cannot reach. This occurs through:

• The activation of antigen-specific cytotoxic T cells that induce apoptosis of cells displaying foreign antigens or derived peptides on their surface.
• The activation of macrophages and NK cells, enabling them to destroy intracellular pathogens.
• The stimulation of cytokine production that further mediates the effective immune response.
  

Take home messages

• A strong immune system is crucial for optimal cattle performance, as it enables to fight against health challenges like pathogens, injuries, and stress.
• The skin and mucosal surfaces serve as the primary defence against most microorganisms. When these barriers are breached, the innate immune system responds rapidly—within minutes to hours—to prevent infection and activate the adaptive immune response.
• The innate immune response is not antigen-specific and has no immunologic memory, i.e., it cannot recognize the same pathogen upon subsequent exposure.
  If the innate immune system is unable to clear infectious agents, the adaptive immune system is triggered. An effective adaptative response usually develops within 2 to 3 weeks, is highly specific to the pathogen and can offer long-lasting protection.
• The cells of the adaptative immune system include B cells and T cells. B cells are the main drivers of humoral or antibody-mediated immunity, whereas T cells are the mediators of cellular immunity, which defend against most viruses and those organisms that infiltrate into cells where antibodies and complement cannot reach.

References

Tizard IR. Veterinary Immunology, 11th Edition, 2024. W B Saunders Co Ltd. ISBN: 9780443109751

Marshall JS, Warrington R, Watson W, Kim HL. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2018 Sep 12;14(Suppl 2):49. 

Anaya JM, Shoenfeld Y, Rojas-Villarraga A, Levy RA, Cervera R, editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18. PMID: 29087650.