T Dependent Antigen and T Independent Antigen

T-dependent antigens are the antigens which need the help of CD4+ helper T cells for complete activation of B cells. These antigens are mostly soluble or particulate proteins. They produce strong and long lasting immune response.

When B cell comes in contact with T-dependent antigen, the antigen binds with B cell receptor (BCR). Then the antigen is taken inside the B cell and broken into small peptide fragments. These peptides are presented on the surface of B cell with MHC class II molecules.

The helper T cell recognizes this presented peptide and gives second activation signal to B cell. This occurs by direct cell contact through CD40-CD40L interaction and also by release of cytokines. These signals help the B cell to divide and differentiate.

During this process, B cells enter into germinal centers and undergo rapid proliferation. They also perform class switching and produce high quality antibodies like IgG, IgA and IgE. It also forms long lived memory B cells, which give protection during future infection.

T-independent antigens are the antigens which can activate B cells without help of T cells. These antigens are mostly non-protein molecules. They give fast immune response but the response is usually weak and short lived.

TI-1 antigens are mitogenic antigens. Example is bacterial lipopolysaccharide (LPS). They can activate B cells through BCR and also through non-specific receptors like Toll-like receptors (TLRs).

TI-2 antigens are large molecules with repeated structural units. Example is bacterial capsular polysaccharide. These repeated structures cross-link many B cell receptors at the same time and produce activation signal without T cell help.

The response to T-independent antigens mainly produces low affinity IgM antibody. It shows little affinity maturation and usually does not produce strong immunological memory.

Because of weak memory response, conjugate vaccines are used in many cases. In this, the T-independent polysaccharide antigen is linked with a strong protein carrier. This converts the antigen into T-dependent antigen.

This helps in recruitment of helper T cells and gives stronger immune response. It produces high affinity antibodies and long lasting memory B cells against capsulated bacterial pathogens.

Basic Characteristics of T-Dependent and T-Independent Antigens

T-Dependent Antigens

• T-dependent antigens are mainly soluble or particulate proteins. These antigens cannot activate B cells completely by themselves.
• These antigens need the help of CD4+ helper T cells for full activation of B cells. So they are called T-dependent antigens.
• In this reaction, B cell binds the antigen through B cell receptor (BCR). Then the antigen is taken inside the B cell and processed into small peptide fragments.
• The processed peptide fragments are presented on the surface of B cell with MHC class II molecules. Then helper T cell recognizes this peptide and gives activation signals.
• The second signal is given by binding of CD40 on B cell with CD40 ligand (CD40L) on T cell. The T cell also releases cytokines like IL-4 and IL-5.
• These antigens cause isotype switching in B cells. So antibodies like IgG, IgA and IgE are produced instead of only IgM.
• T-dependent antigens produce strong germinal center reaction. In this process, B cells undergo somatic hypermutation and affinity maturation.
• These antigens produce high affinity and more specific antibodies. The immune response is strong, refined and long lasting.
• T-dependent antigens form long lived memory B cells and plasma cells. So they give long term protection during repeated infection.

T-Independent Antigens

• T-independent antigens are antigens which can stimulate B cells directly without the help of helper T cells.
• These antigens give rapid immune response. But the response is generally weak, less refined and short lived.
• T-independent antigens mostly produce IgM antibodies. They show little or no affinity maturation and poor immunological memory.
• TI-1 antigens are mitogenic substances. Examples are bacterial lipopolysaccharide (LPS), viral RNA and CpG DNA.
• TI-1 antigens activate B cells by binding with Toll-like receptors (TLRs) along with B cell receptor (BCR).
• At high concentration, TI-1 antigens act as polyclonal B cell activators. They can stimulate many B cells without their specific antigen specificity.
• TI-2 antigens are large non-protein molecules with repeated structure. Examples are bacterial capsular polysaccharides and some polymeric proteins.
• TI-2 antigens activate mature B cells by cross-linking many B cell receptors (BCRs) at the same time.
• TI-2 antigens may need help from complement system. C3d binds with CD21 receptor on B cells and lowers the activation threshold.
• T-independent antigens give weak response in infants and young children below 2 years. This is because their marginal zone B cells are not fully mature and CD21 expression is low.

Classification of T-Independent Antigens

1. Type 1 Thymus-Independent Antigens (TI-1 antigens)

1. Chemical nature – TI-1 antigens are mainly bacterial cell wall components. The important example is lipopolysaccharide (LPS).
2. Activation mechanism – TI-1 antigens have intrinsic ability to stimulate B cells directly. They can induce B cell division without the help of T cells.
3. High concentration effect – At high concentration, TI-1 antigens act as polyclonal B cell mitogens. They can stimulate most B cells to proliferate and differentiate, without depending on their specific antigen receptors.
4. Low concentration effect – At low concentration, TI-1 antigens activate only the specific B cells which bind with them through their antigen receptor.
5. Immune response – TI-1 antigens produce rapid antibody response. But they are poor in isotype switching, affinity maturation and formation of memory B cells.

2. Type 2 Thymus-Independent Antigens (TI-2 antigens)

1. Chemical nature – TI-2 antigens are large molecules with highly repetitive structures. Important examples are bacterial capsular polysaccharides and polymeric proteins.
2. Activation mechanism – TI-2 antigens do not have intrinsic B cell stimulating activity by themselves. They activate mature B cells by binding and cross-linking many B cell receptors (BCRs) at the same time.
3. B cell requirement – TI-2 antigens can activate only mature B cells. Immature B cells become anergic after exposure to repetitive epitopes.
4. Age limitation – Young infants do not give proper response to polysaccharide TI-2 antigens. This is because their mature B cell response is not fully developed.
5. Immune response – TI-2 antigens are important for quick defense against encapsulated bacteria. They can induce IgM and limited IgG antibodies, but do not produce proper affinity maturation and strong immunological memory.

Structure and Nature of T-Dependent Antigens

• T-dependent antigens (TD antigens) are mainly protein in nature. They are usually soluble protein, monomeric protein or particulate protein antigens.
• TD antigens must have such molecular nature that can be taken inside the B cell. After uptake, the antigen is broken into small peptide fragments.
• The processed peptide fragments of TD antigen are loaded on MHC class II molecules. Then these peptide-MHC complex are shown on the surface of B cell.
• TD antigens need help of CD4+ helper T cells. So their structure must allow antigen processing and presentation to the helper T cell.
• The structure of TD antigen supports linked recognition. It means the same antigen complex contains a B cell epitope and also a peptide part for T cell recognition.
• The surface epitope of TD antigen binds with B cell receptor (BCR). This binding helps the B cell to internalize the whole antigen molecule.
• The internal or distinct peptide sequence of the same antigen is processed and presented to T cell receptor (TCR) through MHC class II.
• B cell and T cell do not need to recognize the same epitope. But the peptide recognized by T cell must be a physical part of the same macromolecular antigen which is taken up by the B cell.
• Small chemical groups called haptens cannot produce T-dependent response by themselves. They need to be attached with an immunogenic carrier protein.
• In hapten-carrier conjugate, the hapten binds with BCR and the carrier protein gives peptide fragments for MHC class II presentation. This helps in recruitment of helper T cells.
• Bacterial capsular polysaccharides are generally not T-dependent in nature. But when they are chemically linked with a protein carrier, they are converted into TD antigens.
• Some bacterial zwitterionic polysaccharides (ZPSs) are rare non-protein antigens which can act as T-dependent antigens naturally.
• ZPSs contain alternating positive and negative charge groups on adjacent monosaccharides. These are called cationic and anionic charge motifs.
• Due to these alternating charges, ZPSs form a helical conformation. This structure resembles protein α-helix.
• The fragments of ZPSs can bind directly into the groove of MHC class II molecules. Then they engage CD4+ T cell receptor without needing any protein carrier.

Structure and Nature of T-Independent Antigens

• T-independent antigens (TI antigens) are mainly non-protein microbial substances. These include large polysaccharides, lipids and nucleic acids.
• TI antigens have such structure that can stimulate B cells directly. They produce antibody response without direct help of helper T cells.
• TI antigens usually give rapid immune response. But the response is not very strong and mainly produces IgM antibody.
• TI-1 antigens are mostly pathogen-associated molecular patterns (PAMPs). Common examples are bacterial lipopolysaccharide (LPS), viral RNA and CpG DNA.
• TI-1 antigens have intrinsic mitogenic activity. It means they can directly induce B cell division and proliferation.
• TI-1 antigens can bind with specific B cell receptor (BCR) and also with innate immune receptors like Toll-like receptors (TLRs). Example, LPS can bind with TLR4.
• At high concentration, TI-1 antigens act as polyclonal B cell activators. They can stimulate many B cells, without depending on the specific antigen receptor of each B cell.
• At low concentration, TI-1 antigens activate only those B cells which can bind the antigen by their specific BCR.
• TI-2 antigens are large polymeric molecules with repeated structure. These are mostly non-protein antigens like bacterial capsular polysaccharides, polymeric proteins like flagellin and hapten-Ficoll.
• TI-2 antigens generally need high molecular weight, about 100,000 Da or more, for proper activity. Their repeated epitopes are arranged with proper spacing on the molecule.
• TI-2 antigens do not have intrinsic mitogenic activity. So they cannot activate many B cells in non-specific polyclonal manner like TI-1 antigens.
• TI-2 antigens activate B cells by binding and cross-linking many B cell receptors (BCRs) at same time. This gives strong signal to the B cell.
• About 10 to 20 membrane-bound immunoglobulins must be cross-linked for giving enough activation signal. This signal helps to bypass the need of T cell help.
• TI-2 antigens like polysaccharides can also bind complement products such as C3d. The C3d then binds with CD21 (CR2) receptor on B cell.
• Binding of C3d with CD21 gives an additional signal to the B cell. It lowers the activation threshold and helps in better activation of mature B cells.

Mechanism of Immune Response to T-Dependent Antigens

• The process starts when a naive B cell comes in contact with a specific protein T-dependent antigen. The antigen binds with surface B cell receptor (BCR).
• After binding, the BCR gives first signal inside the B cell. This signal helps the B cell to start the activation process.
• The antigen bound with BCR is taken inside the B cell by receptor mediated endocytosis.
• Inside the B cell, the protein antigen is broken down into small peptide fragments by protease enzymes.
• The peptide fragments are loaded on MHC class II molecules. Then this peptide-MHC class II complex is shown on the surface of B cell.
• The antigen specific CD4+ helper T cell recognizes this peptide-MHC class II complex by its T cell receptor (TCR).
• CD40 present on B cell binds with CD40 ligand (CD40L) present on helper T cell. This gives the most important second signal for B cell activation.
• Other supporting signals also occur. B7 (CD80/CD86) on B cell binds with CD28 on T cell and helps in proper activation.
• The activated helper T cell releases cytokines toward the B cell. Important cytokines are IL-2, IL-4, IL-5 and IL-21.
• Due to cytokine action, the B cell enters into cell cycle and divides rapidly. Many daughter B cells are formed.
• The activated B cells migrate into lymphoid follicles and form special area called germinal center.
• In the dark zone of germinal center, proliferating B cells undergo somatic hypermutation. Random point mutations occur in antibody genes.
• In the light zone, mutated B cells are tested for better antigen binding. Only B cells with higher antigen affinity get survival signal and this is called affinity maturation.
• Under the effect of helper T cell cytokines like IL-4, IFN-γ and TGF-β, B cells undergo class switch recombination. The antibody changes from IgM to IgG, IgA or IgE.
• Some selected high affinity B cells become plasma cells. These cells produce large amount of high affinity and class switched antibodies.
• Some selected B cells become memory B cells. These cells remain for long time and give rapid strong response during next exposure to same antigen.

Mechanism of Immune Response to T-Independent Antigens

• The process starts when a mature B cell comes in contact with a non-protein T-independent antigen. It may be bacterial lipopolysaccharide (LPS) or repeated capsular polysaccharide.
• The antigen binds directly with surface B cell receptors (BCRs) present on the B cell. This binding starts the first activation signal inside the cell.
• In case of TI-1 antigens, the antigen binds with specific BCR and also binds with innate receptors like Toll-like receptors (TLRs). Example, LPS binds with TLR4.
• In case of TI-2 antigens, the repeated structural units bind with many BCRs at same time. About 10 to 20 BCRs are cross-linked and this gives strong primary signal.
• Since helper T cells are not involved, classical CD40-CD40L interaction does not occur. So the B cell needs second signal from another source.
• In TI-1 antigens, the second signal is provided by TLR stimulation. The signal passes through intracellular adaptor like MyD88 and helps in B cell activation.
• In TI-2 antigens, the second signal is often given by complement system. The antigen is tagged with C3d and this C3d binds with CD21 (CR2) receptor on B cell.
• Binding of C3d with CD21 brings CD19/CD21/CD81 co-receptor complex close to the BCR. This increases the activation signal and lowers the activation threshold.
• The combined signals from BCR, TLR or complement receptor activate intracellular signaling pathways. Enzymes like Syk, Src and Lyn are involved in this process.
• These signals activate transcription factors like NF-κB and AP-1. They help the B cell to enter into active state.
• The activated B cell enters into cell cycle and undergoes clonal proliferation. Many similar B cells are formed from the stimulated B cell.
• At very high concentration, TI-1 antigens act as mitogens. They can cause polyclonal activation and make many B cells divide without their specific antigen receptor.
• The proliferating B cells do not undergo strong germinal center reaction. They directly differentiate into short lived plasma cells.
• The formed plasma cells rapidly secrete large amount of antibody. The antibody is mainly IgM type.
• As there is no T cell cytokine help, somatic hypermutation and affinity maturation are almost absent. Isotype switching is also very limited.
• This response gives quick first line protection against encapsulated blood borne pathogens. But the response is short lived, antibody affinity is low and long lasting memory B cells are generally not formed.

Role of T Helper Cells in T-Dependent Antigen Response

• Specific antigen recognition – CD4+ helper T cells use their T cell receptor (TCR) to recognize specific peptide fragments displayed on MHC class II molecules of B cell. This is called linked recognition, and it ensures that T cell gives help only to the B cell which has taken up the correct antigen.
• Co-stimulatory signal – After recognizing the antigen, the helper T cell expresses CD40 ligand (CD40L) on its surface, which binds with CD40 receptor on the B cell. This direct cell to cell contact gives the essential second activation signal and drives the resting B cell into cell cycle.
• Cytokine secretion – The engaged helper T cell secretes activating cytokines like IL-4, IL-5 and IL-6 in directed manner toward the B cell. These cytokines work together with CD40-CD40L interaction and stimulate rapid B cell proliferation and differentiation into antibody secreting plasma cells.
• Isotype switching – The cytokines released by helper T cell act as instruction for antibody class switching. IL-4 helps B cell to switch into IgG1 or IgE, while IFN-γ directs the B cell to produce IgG2a or IgG3.
• Germinal center reaction – Antigen specific helper T cells migrate with activated B cells into lymphoid follicles and help in formation and maintenance of germinal centers. Inside germinal center, continuous T cell help by CD40L engagement and survival signals like BLyS keeps the rapidly mutating B cells alive, so they undergo affinity maturation and finally become high affinity memory B cells.

Antibody Production Against T-Dependent and T-Independent Antigens

Antibody Production Against T-Dependent Antigens

• In response to T-dependent antigens, the early stage of antibody production mainly gives IgM antibodies. This is the first antibody produced by activated B cells.
• After this, helper T cells give signals to B cells by CD40-CD40L interaction and cytokines such as IL-4, IFN-γ and TGF-β. These signals help the B cell to change from IgM production to other antibody classes.
• Due to class switching, the B cells produce specialized antibodies like IgG, IgA and IgE. These antibodies are more useful in different immune functions.
• In germinal centers, proliferating B cells undergo somatic hypermutation. The B cells which bind antigen strongly are selected and this produces high affinity antibodies.
• The response finally forms long lived plasma cells and memory B cells. During second exposure to same antigen, these memory cells produce faster and stronger antibody response.
• The secondary response against T-dependent antigens is mainly made of high affinity IgG antibodies. It is larger in amount and more effective than primary response.

Antibody Production Against T-Independent Antigens

• In response to T-independent antigens, antibody production is rapid. But the antibody response is generally weak and lower in quality than T-dependent antigen response.
• Since this response occurs without direct helper T cell help, proper affinity maturation does not occur. So the produced antibodies usually have lower affinity.
• This response generally does not produce strong and long lasting immunological memory. Memory B cells are absent or very poor.
• In response to TI-1 antigens, the antibody produced is mainly IgM. These antigens are highly inefficient in inducing isotype switching.
• In response to TI-2 antigens, the main antibody produced is also IgM. But these antigens may induce limited class switching.
• Due to limited class switching, TI-2 antigens can produce some IgG antibodies along with IgM. These antibodies help in coating encapsulated bacteria and make them easy for destruction by phagocytes.

Immunological Memory in T-Dependent and T-Independent Responses

Immunological Memory in T-Dependent Responses

• In T-dependent response, long lived memory B cells and long lived plasma cells are formed. These cells remain in the body and give long lasting immunity.
• Formation of memory cells needs help from CD4+ helper T cells. This help is given by direct cell contact and cytokine signals.
• T-dependent response occurs through formation of germinal centers in lymphoid tissues. In germinal center, B cells divide, mutate and get selected.
• During this process, B cells undergo somatic hypermutation and isotype switching. So the memory B cells formed are better in antigen recognition.
• During second exposure to same antigen, these memory cells give faster and stronger immune response. The antibody produced is mainly high affinity IgG.
• The secondary response is larger in amount than primary response. It gives better protection against future infection by same pathogen.

Immunological Memory in T-Independent Responses

• In T-independent response, the immune response is rapid but does not form strong memory. It is mainly useful for quick first line defense.
• T-independent antigens usually fail to generate long lasting immunological memory. Memory B cells are absent or very weak.
• Without helper T cell signals, B cells do not form proper germinal center reaction. So the response becomes short lived.
• The activated B cells mostly differentiate into short lived plasma cells. These cells produce antibody for short period only.
• The antibody produced is mainly low affinity IgM. Proper affinity maturation does not occur in this response.
• Because of poor memory and low affinity antibody, repeated exposure to the same T-independent antigen does not give very strong secondary response.

Overcoming T-Independent Limitation by Conjugate Vaccines

• Many T-independent antigens, such as bacterial capsular polysaccharides, do not produce good memory response. So they are linked chemically with a protein carrier.
• This protein carrier converts the polysaccharide antigen into T-dependent antigen like form. The B cell binds the polysaccharide part and processes the attached protein carrier.
• The protein peptide is presented to helper T cells by MHC class II molecules. Then T cell help is recruited for the same antigen complex.
• Due to T cell help, germinal center reaction occurs. This leads to formation of high affinity class switched antibodies and strong memory B cells.
• Thus, conjugate vaccines help to produce long lasting immunity against antigens which normally give weak and temporary T-independent response.

Examples of T-Dependent and T-Independent Antigens

T-Dependent (TD) Antigens

• Foreign proteins and toxoids
  • Tetanus toxoid (TT).
  • Diphtheria toxoid (DT) and its non-toxic variant CRM197.
  • Pseudomonas aeruginosa exotoxin A (rEPA).
  • Haemophilus influenzae protein D (HiD).
  • Hen egg lysozyme.
  • Keyhole limpet hemocyanin (KLH), a large metalloprotein used as a carrier.
• Zwitterionic polysaccharides (ZPSs)
  • Polysaccharide A1 (PS-A1), PS-A2 and Polysaccharide B (PS-B) from Bacteroides fragilis.
  • MM-ZPS from Morganella morganii.
  • Sp1 from Streptococcus pneumoniae.

T-Independent (TI) Antigens

• Type 1 (TI-1) antigens
  • Bacterial lipopolysaccharide (LPS).
  • Viral RNAs.
  • Microbial CpG DNA.
• Type 2 (TI-2) antigens
  • Bacterial capsular polysaccharides from encapsulated bacteria like Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis.
  • Polymeric protein antigens such as flagellin.
  • Hapten-Ficoll molecules such as TNP-Ficoll and DNP-Ficoll.
  • Dextran B512, a high molecular weight carbohydrate polymer.

Clinical and Immunological Significance of T-Dependent and T-Independent Antigens

T-Dependent (TD) Antigens

• T-dependent antigens produce high quality immune response. They help B cells to enter into germinal center reaction, where somatic hypermutation and affinity maturation occurs.
• These antigens produce highly specific and high affinity antibodies. So the antibody response is more strong and more protective.
• T-dependent response forms long lived memory B cells and plasma cells. These cells may remain in the body for long time and give lasting immunity.
• The long lived plasma cells migrate to bone marrow and continue antibody production. This gives protection during future exposure to same pathogen.
• T-dependent antigens cause isotype switching under the effect of T cell cytokines. So B cells can produce IgG, IgA and IgE according to the need of immune response.
• These antigens are important in routine immunization. Vaccines like tetanus toxoid and diphtheria toxoid are based on strong T-dependent antigen response.
• T-dependent proteins are used as carriers in conjugate vaccines. They convert weak polysaccharide antigen into strong antigen and help to produce memory response.

T-Independent (TI) Antigens

• T-independent antigens give rapid first line antibody response. This response does not need previous activation and expansion of helper T cells.
• The antibody formed is mainly IgM. It gives fast protection against blood borne pathogens.
• TI-2 antigens are important against encapsulated bacteria. These include Streptococcus pneumoniae, Haemophilus influenzae type b and Neisseria meningitidis.
• Encapsulated bacteria have thick polysaccharide capsule. This capsule helps them to escape phagocytosis, so rapidly formed TI antibodies coat them and help in opsonization.
• T-independent response is weak in infants and young children below 2 years. Their marginal zone B cells are not fully developed and CD21 expression is low.
• Due to weak TI-2 response, infants are more susceptible to serious infections like meningitis and pneumonia caused by encapsulated bacteria.
• Patients without functional spleen are also weak in T-independent response. This may occur after splenectomy or in sickle cell anemia.
• Some immunodeficient patients like Wiskott-Aldrich syndrome also cannot produce proper TI response. So they become more susceptible to severe encapsulated bacterial infection.
• High amount of TI-1 antigens like bacterial lipopolysaccharide (LPS) can act as strong mitogens. They may cause non-specific polyclonal activation of many B cells.
• This polyclonal activation may occur in severe systemic infection. It is one important factor in harmful immune activation during sepsis.
• Pure T-independent polysaccharide vaccines do not produce strong memory and do not protect infants properly. This limitation led to development of conjugate vaccines.
• In conjugate vaccines, weak TI polysaccharide is chemically linked with strong TD protein carrier. This makes the immune system produce T-dependent response, high affinity antibody and long lasting memory.

Differences Between T-Dependent and T-Independent Antigens

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