Activation of B cells requires two signals. Depending on the nature of the antigen, B-cell activation proceeds by two different routes, one dependent on helper T cells (TH cells), the other not. In the case of T dependent antigen the interaction between CD40 of B Cells and CD40 ligand of T cells gives second signal but in T independent antigen, cross-linking of membrane bound immunoglobulin to polymeric carbohydrate gives the needed signal.
The B-cell response to thymus-dependent (TD) antigens requires direct contact with TH cells, not simply exposure to TH-derived cytokines.
Antigens that can activate B cells in the absence of this kind of direct participation by TH cells are known as thymus-independent (TI) antigens. TI antigens are divided into types 1 and 2, and they activate B cells by different mechanisms whereas polymeric proteins e.g., bacterial flagellin acts as Type 2 thymus-independent (TI-2) antigens.
T Independent (TI) Antigen
A typical large polysaccharide is made up of repeating sequences of few simple sugars so it has multiple copies of identical antigenic determinants.
When a specific naïve B cells come in contact with such antigens, these antigenic determinants bind the surface IgM and IgD receptors. This binding leads to clustering of surface immunoglobulins which generates a signal, strong enough to activate the naïve B cells. This activated B cells produces and releases first immunoglobulin i.e. IgM.
Most TI-1 antigens are polyclonal B-cell activators (mitogens); i.e. they are able to activate B cells regardless of their antigenic specificity. At higher concentrations, some TI-1 antigens will stimulate proliferation and antibody secretion by as many as one third of all B cells but in lower concentrations of TI-1 antigens, only those B cells specific for epitopes of the antigen will be activated.
TI-2 antigens activate B cells by extensive crosslinking of membrane bound immunoglobulin (mIg) receptor.
Unlike TI-1 antigens, TI-2 antigens do not act as polyclonal activator, activate only mature B cells and may require cytokines derived from TH cells.
Main features of T Independent Antigen (Ti-Ag)
- Antigens that stimulate B-cells directly, without co-stimulation by helper T-cells
- Usually polysaccharides or lipopolysaccharides (e.g. bacterial capsules)
- Cross link antigen receptors on the surface of B-cells to activate them
- Don’t generate strong immune response (no memory cells, IgM is the only antibody class produced, and the immunity doesn’t last long).
T Dependent Antigen (Td-Ag)
Humoral response to protein and most other antigens requires interaction of B cells with helper T cells. These are thymus-dependent or simply T-dependent (TD) responses. B cell activation by T dependent antigens require contact dependent help delivered by the interaction between CD40 on B cells and CD40L on activated TH cells.
Main steps during B-cell activation by a thymus-dependent antigen:
- Soluble protein antigens which bind to membrane bound immunoglobulin on the surface of B Cell are internalized, processed and are displayed as peptide-MHC-II complexes.
- TH cell recognizes class II MHC-antigen complex on B-cell surface via TCR. It also interacts with costimulatory molecule B7 via CD28. These interactions activates TH cell. Activated TH cells produces various cytokines.
- TH cell begins to express CD40L and interacts with CD40 of the B Cell. The interaction between CD40 and CD40L provides second signal to activate B cell.
- B cells begins to express receptors for various cytokines and binds to cytokines released from TH cells. Which activates B cell and differentiates them to plasma cells.
- The activated B-cell clonally proliferates to produce a population of plasma cells and memory cells, which all recognize the same antigen
This CD40/CD40L interaction is essential for B-cell survival, the formation of germinal centers, the generation of memory-cell populations and somatic hypermutation (for affinity maturation).
Difference between T dependent Antigen and T independent Antigen
|T dependent (TD) Antigen|| |
T independent Antigen
|Soluble proteins|| |
Bacterial cell wall components Lipopolysaccharide (LPS), Capsular polysaccharide, flagella etc.
Antigen is processed and displayed in the surface of Antigen Presenting Cells (B Cells) in association with MHC-II.
Antigen processing is not needed
Immunogenic over wide range of dose
Dose dependent immunogenicity
|No polyclonal activation i.e. Activate B cells monoclonally|| |
Polyclonal activation of B cells occur in high doses of Type-I TI Antigens
|Immunologic memory present|| |
No Immunologic Memory
|Affinity Maturation- Yes||Affinity Maturation- No|
|Isotype Switching occurs (i.e. antibodies of all classes are produced)||No Isotype switching |
( Antibody response is restricted to IgM and IgG3)
|Activate mature B cells only|| |
Activate both mature and immature B cells
References and further reading:
- Cellular and Molecular Immunology, 9th Edition
- Kuby Immunology, 7th Edition
- Roitt’s Essential Immunology, 13th Edition