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T independent antigen elicits antibody production by B lymphocytes without T lymphocyte involvement. There are 2 distinct subgroups of TI antigens, different in mechanism of activating B lymphocytes. TI-1 antigen, which has an activity that can directly activate B cells and TI-2 antigen, which has highly repetitive structure and causes simultaneous cross-linking of specific B cell receptors (BCR) on B lymphocyte. The most commonly released isotype of antibodies in this type of immune reaction is low affinity IgM.^[1]

For most protein antigens, the production of antibodies by B lymphocytes is dependent on stimulation of helper T cells. However bacterial polysaccharides and lipopolysaccharides, and some polymeric proteins, can stimulate B lymphocytes without involvement of helper T cells. The non-protein microbial antigens cannot stimulate classical T cell response by themselves, but they are able to elicit the production of antibodies, so that is why we call them T cell or thymus independent antigens.^[2]

T independent antigens are divided into 2 classes by the mechanism of activating B cells.

TI-1 antigens have an intrinsic B cell activating activity, that can directly cause proliferation and differentiation of B lymphocytes without T cell stimulation and independently of their BCR specificity. TI-1 antigens activate B-cells via Toll like receptors, which are expressed in humans on the surface of B lymphocytes after BCR stimulation. TI-1 antigens are classified as B-cell mitogens, because they induce numerous cell divisions. In higher concentrations, TI-1 antigens bind to BCR and TLR of various clones of B lymphocytes, which leads to production of multiclonal antibodies. But when the concentration of TI-1 is lower, it can activate only B lymphocytes with specific binding of TI-1 on their BCR, and leads to production of monoclonal antibodies.^[1] This part of immune response may be important in some early stages of infection by extracellular pathogens, because it is rapidly activated and does not require T cell help or clonal maturation and expansion. An example of TI-1 antigen is lipopolysaccharide (LPS) or bacterial DNA.^[2]

Second group of TI antigens consists mainly of highly repetitive surface structures (epitopes) of encapsulated bacteria. They do not have an intrinsic B-cell activating activity. The activation of B lymphocytes is caused by cross-linking of a critical number of B cell receptors, which leads to accumulation of BCRs and cross activation of these receptors. It results in proliferation and differentiation of B lymphocytes and production of antibodies. TI-2 antigens can activate only mature B lymphocytes. Immature B cells are anergized, so they do not elicit any immune response. That may explain why children up to 5 years are not capable of producing effective antibodies against polysaccharide antigens, as the majority of their B cell population is immature.^[2] Even though the response on TI antigens is not dependent on T lymphocytes, there are some cytokines, produced mainly by T lymphocytes and natural killer (NK) cells, necessary for eliciting reaction against these antigens. The most necessary are interleukin 2 (IL-2), interleukin 3 (IL-3) and interferon γ (IFN-γ).^[1] Moreover, additional stimulation by dendritic cells (DC) and macrophages is required.^[2]