B cell Activation by T Independent & T Dependent Antigens-Dr C R Meera

During humoral immune response, Ab production is brought about by B lymphocytes. Based on the ability to induce Ab formation, antigens can be classified into T independent and T dependent antigens. Some antigens can directly induce the B cells to produce the Abs and are called T Independent Ans. However, some Ans require the help of T lymohocytes for the production of Abs from B cells. These Ans are called T Dependent Ans.

1. T- Independent & T- Dependent Antigens – B cell Activation Dr C R Meera, M Sc ; Ph D, Assistant Professor & HOD, Department of Microbiology, St. Mary’s College, Thrissur-20, Kerala, India.

2. What are TI & TD Antigens? TI & TD Antigens- B Cell Activation; Dr C R Meera, St Mary’s College, TCR, Kerala, India During humoral immune response , Ab production is brought about by B lymphocytes . Based on the ability to induce Ab formation - T independent and T dependent antigens TI Antigens - T Independent Antigens TD Antigens - T Dependent Antigens Some Ans can directly induce the B cells to produce the Abs - TI Ans Some Ans require the help of T lymohocytes for the production of Abs from B cells- TD Ans . Image courtesy: studyblue.com

3. T Independent (TI) Antigens TI & TD Antigens- B Cell Activation ; Dr C R Meera, St Mary’s College, TCR, Kerala, India Most of the protein Ans require the help of T cells for the production of Abs Ans like bacterial capsular polysaccharides, bacterial lipopolysaccharides , polymeric proteins like flagellin - directly stimulate the B Cells, without the help of T cells - T Cell or Thymus Independent (TI) antigens TI) antigens- Activate B cells with out An processing and presentation to the T cells They are structurally simple and carry repeating epitopes These repeating epitopes cross link the BCRs and act as first signal of activation. For complete activation of B cells a dual signal is required, the second signal usually comes from T cells In TI activation, second signal should come from sources other than T cells

4. TI & TD Antigens- B Cell Activation ; Dr C R Meera, St Mary’s College, TCR, Kerala, India TI Ans are metabolized slowly and remain in the body for long periods There are two types of TI Antigens- TI-1 antigens and TI-2 antigens TI-1 are usually b acterial lipopolysaccharides (LPS) which are mitogenic to B cells First signal - Binding of TI Ans + BCR Second signal -Binding to the lipid moiety of LPS with CD14/TLR 4 of B cells Toll-like receptors - are receptor proteins help in the recognition of pathogens TLRs are found on : Leukocytes (Dendritic cells, Macrophages, Natural Killer cells) T cells & b cells Epithelial,  endothelial cells and  fibroblasts TI-1 Antigens B Cell LPS Image courtesy: slideplayer.com

5. TI & TD Antigens- B Cell Activation ; Dr C R Meera, St Mary’s College, TCR, Kerala, India TI – 2 Antigens TI-2 antigens are compounds like polysaccharides without mitogenic properties & flagellin They contain multiple repeats of limited number of sugar molecules cause excessive cross linking of BCRs This will deliver strong signals that can compensate the need for co-stimulatory signals from T cells Second signal - Interactions of  toll-like receptors (TLRs) with PAMPs  or interactions with factors from the complement system. PAMPs - Pathogen Associated Molecular Patterns found on infectious agents which are recognized by TLRs Image courtesy: slideplayer.com B Cell PS or flagellin

6. TI & TD Antigens- B Cell Activation ; Dr C R Meera, St Mary’s College, TCR, Kerala, India Once the B cells are activated, they undergo clonal proliferation and daughter cells differentiate into plasma cells Plasma cells  are antibody factories that secrete large quantities of antibodies Abs produced by TI Ans are mainly IgM Abs No production of memory cells and no immunological memory Hence immune response is effective in primary infection and also short lived Immune response by TI Ans is dose dependent. Means, too little An is not immunogenic and too much An cause immunological tolerance B Cell Activation by TI Antigens

7. TI & TD Antigens- B Cell Activation ; Dr C R Meera, St Mary’s College, TCR, Kerala, India T Dependent (TD) Antigens TD Antigens - Require the participation of T lymphocytes for the stimulation of B cells T cells are of two types. Helper T cells (T H ) or CD 4+ cells and Cytotoxic T cells (T C ) or CD 8+ cells. T H cells are involved in B cell activation by TD antigens. TD antigens are structurally complex molecules like serum proteins, protein- hapten complex, erythrocytes etc. Activation of B cells by TD antigens is more complex, but results in stronger response with immunological memory TD antigens have to be first processed by the An processing/ presenting cells (APC )

8. TI & TD Antigens- B Cell Activation ; Dr C R Meera, St Mary’s College, TCR, Kerala, India Antigen Processing Cells (APCs) An processing/presenting cells- Macrophages , dendritic cells and B cells These cells capture An and present them to T lymphocytes APCs have 2 unique properties They express MHC Class II molecules on their surface. They can also produce co-stimulatory signals necessary to activate T H cells APCs first internalize the An by phagocytosis or endocytosis Then APCs display part of An bound to MHC Class II molecules on their surface membrane. T H cells can recognise only those Ans that are presented or attached to MHC class II Image courtesy: veteriankey.com

9. TI & TD Antigens- B Cell Activation ; Dr C R Meera, St Mary’s College, TCR, Kerala, India B Cell Activation by TD Antigens I signal - If B cell is acting as the APC, then the first signal is binding of An and BCR ( B cell will internalise the An, process it and present part of An on its surface along with MHC Class II which will be recognized by T H cells) II signal - T Cell Receptor (TCR)-CD3 complex on the surface of T Cell + [MHC Class II – An] expressed on the surface of B cells. CD4 molecule of T cell also bind to a specific portion on the MHC molecule of B cell to make the binding more effective. This binding of B cell/APC to T H cell is called “linked recognition”.

10. TI & TD Antigens- B Cell Activation ; Dr C R Meera, St Mary’s College, TCR, Kerala, India B Cell Activation by TD Antigens Additional activation of T H cells are brought about co-stimulatory signals produced by the APCs Co-stimulatory signals CD 28 on T H cells binds to CD 80 (B7-1) or CD86 (B7-2) membrane proteins on APC. T H cells also start expressing CD40 Ligand (CD40L) which will interact with complementary CD40 of the B cell

11. TI & TD Antigens- B Cell Activation ; Dr C R Meera, St Mary’s College, TCR, Kerala, India B Cell Activation by TD Antigens Activated T H cells secrete T cell growth factor or Interleukin-2 (IL-2) which will act on the T H cell itself and initiate its proliferation. Proliferated T H cells are called naïve T cells or T H cells Proliferated T H cells secrete IL-2, IL-4, IFN-γ etc B cells begin to express receptors for various cytokines, bind to cytokines released by T H cells and thus B cells get activated

12. TI & TD Antigens- B Cell Activation ; Dr C R Meera, St Mary’s College, TCR, Kerala, India B Cell Activation by TD Antigens The activated B-cell proliferates to produce plasma cells (Effector B cells) and secrete Abs Initially IgM are the Abs produced by plasma cells After several rounds of proliferation, B cells differentiate to form memory B cells After initial secretion of IgM , cytokines secreted by T H cells stimulate the plasma cells to switch from IgM production to production of  IgG , IgA, or  IgE This process is called  class switching or  isotype switching Class switching is due to genetic rearrangement of gene segments encoding the constant region of Abs

13. TI & TD Antigens- B Cell Activation ; Dr C R Meera, St Mary’s College, TCR, Kerala, India Differences between TI & TD Antigens TI Antigens TD Antigens Structurally simple & composed of limited number of repeating epitopes Structurally complex   Molecules like bacterial capsular polysaccharides, bacterial lipopolysaccharides and some polymeric proteins like flagellar protein flagellin Molecules like serum proteins, protein- hapten complex, erythrocytes etc Immune response is dose dependent. Immunogenic over wide dose range. Do not readily cause tolerance Do not require preliminary processing by APCs Require preliminary processing by APCs and presented along with MHC class II molecules on the surface of APC Ab response limited to IgM and no isotype switching Isotype switching occurs and induce formation of almost all isotypes like IgM , IgG , IgA & IgE Week response & no immunological memory Strong response with immunological memory Metabolized slowly and remain in body for long periods Metabolized rapidly in the body

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