cells or clear pathogens, but, in essence "manage" the immune response, by directing other cells to perform these tasks. helper t cells express t cell receptors (tcr) that recognize antigen bound to class ii mhc molecules. the activation of a naive helper t-cell causes it to release cytokines, which influences the activity of many cell types, including the apc (antigen-presenting cell) that activated it. helper t-cells require a much milder activation stimulus than cytotoxic t cells. helper t cells can provide extra signals that "help" activate cytotoxic cells. th1 and th2: helper t cell responses classically, two types of effector cd4+ t helper cell responses can be induced by a professional apc, designated th1 and th2, each designed to eliminate different types of pathogens. the factors that dictate whether an infection triggers a th1 or th2 type response are not fully understood, but the response generated does play an important role in the clearance of different pathogens. the th1 response is characterized by the production of interferon-gamma, which activates the bactericidal activities of macrophages, and induces b cells to make opsonizing (marking for phagocytosis) and complement-fixing antibodies, and leads to cell-mediated immunity. in general, th1 responses are more effective against intracellular pathogens (viruses and bacteria that are inside host cells). the th2 response is characterized by the release of interleukin 5, which induces eosinophils in the clearance of parasites. th2 also produce interleukin 4, which facilitates b cell isotype switching. in general, th2 responses are more effective against extracellular bacteria, parasites including helminths and toxins. like cytotoxic t cells, most of the cd4+ helper cells die on resolution of infection, with a few remaining as cd4+ memory cells. increasingly, there is strong evidence from mouse and human-based scientific studies of a broader diversity in cd4+ effector t helper cell subsets. regulatory t (treg) cells, have been identified as important negative regulators of adaptive immunity as they limit and suppress the immune system to control aberrant immune responses to self-antigens; an important mechanism in controlling the development of autoimmune diseases. follicular helper t (tfh) cells are another distinct population of effector cd4+ t cells that develop from naive t cells post-antigen activation. tfh cells are specialized in helping b cell humoral immunity as they are uniquely capable of migrating to follicular b cells in secondary lymphoid organs and provide them positive paracrine signals to enable the generation and recall production of high-quality affinity-matured antibodies. similar to tregs, tfh cells also play a role in immunological tolerance as an abnormal expansion of tfh cell numbers can lead to unrestricted autoreactive antibody production causing severe systemic autoimmune disorders. the relevance of cd4+ t helper cells is highlighted during an hiv infection. hiv is able to subvert the immune system by specifically attacking the cd4+ t cells, precisely the cells that could drive the clearance of the virus, but also the cells that drive immunity against all other pathogens encountered during an organism's lifetime. gamma delta t cells main article: gamma delta t cell gamma delta t cells (γδ t cells) possess an alternative t cell receptor (tcr) as opposed to cd4+ and cd8+ αβ t cells and share characteristics of helper t cells, cytotoxic t cells and natural killer cells. like other 'unconventional' t cell subsets bearing invariant tcrs, such as cd1d-restricted natural killer t cells, γδ t cells exhibit characteristics that place them at the border between innate and acquired immunity. on one hand, γδ t cells may be considered a component of adaptive immunity in that they rearrange tcr genes via v(d)j recombination, which also produces junctional diversity, and develop a memory phenotype. on the other hand, however, the various subsets may also be considered part of the innate immune system where a restricted tcr or nk receptors may be used as a pattern recognition receptor. for example, according to this paradigm, large numbers of vγ9/vδ2 t cells respond within hours to common molecules produced by microbes, and highly restricted intraepithelial vδ1 t cells respond to stressed epithelial cells. b lymphocytes and antibody production main articles: b cell and humoral immunity the b lymphocyte activation pathway. b cells function to protect the host by producing antibodies that identify and neutralize foreign objects like bacteria and viruses. b cells are the major cells involved in the creation of antibodies that circulate in blood plasma and lymph, known as humoral immunity. antibodies (also known as immunoglobulin, ig), are large y-shaped proteins used by the immune system to identify and neutralize foreign objects. in mammals, there are five types of antibody: iga, igd, ige, igg, and igm, differing in biological properties; each has evolved to handle different kinds of antigens. upon activation, b cells produce antibodies, each of which recognize a unique antigen, and neutralizing specific pathogens. antigen and antibody binding would cause five different protective mechanisms: agglutination: reduces number of infectious units to be dealt with activation of complement: cause inflammation and cell lysis opsonization: coating antigen with antibody enhances phagocytosis antibody-dependent cell-mediated cytotoxicity: antibodies attached to target cell cause destruction by macrophages, eosinophils, and nk cells neutralization: blocks adhesion of bacteria and viruses to mucosa like the t cell, b cells express a unique b cell receptor (bcr), in this case, a membrane-bound antibody molecule. all the bcr of any one clone of b cells recognizes and binds to only one particular antigen. a critical difference between b cells and t cells is how each cell "sees" an antigen. t cells recognize their cognate antigen in a processed form – as a peptide in the context of an mhc molecule, whereas b cells recognize antigens in their native form. once a b cell encounters its cognate (or specific) antigen (and receives additional signals from a helper t cell (predominately th2 type)), it further differentiates into an effector cell, known as a plasma cell. plasma cells are short-lived cells (2–3 days) that secrete antibodies. these antibodies bind to antigens, making them easier targets for phagocytes, and trigger the complement cascade. about 10% of plasma cells survive to become long-lived antigen-specific memory b cells. already primed to produce specific antibodies, these cells can be called upon to respond quickly if the same pathogen re-infects the host, while the host experiences few, if any, symptoms. alternative systems in jawless vertebrates primitive jawless vertebrates, such as the lamprey and hagfish, have an adaptive immune system that shows 3 different cell lineages, each sharing a common origin with b cells, αβ t cells, and innate-like γδ t cells. instead of the classical antibodies and t cell receptors, these animals possess a large array of molecules called variable lymphocyte receptors (vlrs for short) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of genes. these molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same degree of specificity. in insects for a long time it was thought that insects and other invertebrates possess only innate immune system. however, in recent years some of the basic hallmarks of adaptive immunity have been discovered in insects. those traits are immune memory and specificity. although the hallmarks are present the mechanisms are different from those in vertebrates. immune memory in insects was discovered through the phenomenon of priming. when insects are exposed to non-lethal dose or heat killed bacteria they are able to develop a memory of that infection that allows them to withstand otherwise lethal dose of the same bacteria they were exposed to before. unlike in vertebrates, insects do not possess cells specific for adaptive immunity. instead those mechanisms are mediated by hemocytes. hemocytes function similarly to phagocytes and after priming they are able to more effectively recognize and engulf the pathogen. it was also shown that it is possible to transfer the memory into offspring. for example, in honeybees if the queen is infected with bacteria then the newly born workers have enhanced abilities in fighting with the same bacteria. other experimental model based on red flour beetle also showed pathogen specific primed memory transfer into offspring from both mothers and fathers. most commonly accepted theory of the specificity is based on dscam gene. dscam gene also known as down syndrome cell adhesive molecule is a gene that contains 3 variable ig domains. those domains can be alternatively spliced reaching high numbers of variations. it was shown that after exposure to different pathogens there are different splice forms of dscam produced. after the animals with different splice forms are exposed to the same pathogen only the individuals with the splice form specific for that pathogen survive. other mechanisms supporting the specificity of insect immunity is rna interference (rnai). rnai is a form of antiviral immunity with high specificity. it has several different pathways that all end with the virus being unable to replicate. one of the pathways is sirna in which long double stranded rna is cut into pieces that serve as templates for protein complex ago2-risc that finds and degrades complementary rna of the virus. mirna pathway in cytoplasm binds to ago1-risc complex and functions as a template for viral rna degradation. last one is pirna where small rna binds to the piwi protein family and controls transposones and other mobile elements. despite the research the exact mechanisms responsible for immune priming and specificity in insects are not well described. immunological memory further information: immunity (medical) when b cells and t cells are activated some become memory b cells and some memory t cells. throughout the lifetime of an animal these memory cells form a database of effective b and t lymphocytes. upon interaction with a previously encountered antigen, the appropriate memory cells are selected and activated. in this manner, the second and subsequent exposures to an antigen produce a stronger and faster immune response. this is "adaptive" in the sense that the body's immune system prepares itself for future challenges, but is "maladaptive" of course if the receptors are autoimmune. immunological memory can be in the form of either passive short-term memory or active long-term memory. passive memory passive memory is usually short-term, lasting between a few days and several months. newborn infants have had no prior exposure to microbes and are particularly vulnerable to infection. several layers of passive protection are provided by the mother. in utero, maternal igg is transported directly across the placenta, so that, at birth, human babies have high levels of antibodies, with the same range of antigen specificities as their mother. breast milk contains antibodies (mainly iga) that are transferred to the gut of the infant, protecting against bacterial infections, until the newborn can synthesize its own antibodies. this is passive immunity because the fetus does not actually make any memory cells or antibodies: it only borrows them. short-term passive immunity can also be transferred artificially from one individual to another via antibody-rich serum. active memory in general, active immunity is long-term and can be acquired by infection followed by b cell and t cell activation, or artificially acquired by vaccines, in a process called immunization. immunization historically, infectious disease has been the leading cause of death in the human population. over the last century, two important factors have been developed to combat their spread: sanitation and immunization. immunization (commonly referred to as vaccination) is the deliberate induction of an immune response, and represents the single most effective manipulation of the immune system that scientists have developed. immunizations are successful because they utilize the immune system's natural specificity as well as its inducibility. the principle behind immunization is to introduce an antigen, derived from a disease-causing organism, that stimulates the immune system to develop protective immunity against that organism, but that does not itself cause the pathogenic effects of that organism. an antigen (short for antibody generator), is defined as any substance that binds to a specific antibody and elicits an adaptive immune response. most viral vaccines are based on live attenuated viruses, whereas many bacterial vaccines are based on acellular components of microorganisms, including harmless toxin components. many antigens derived from acellular vaccines do not strongly induce an adaptive response, and most bacterial vaccines require the addition of adjuvants that activate the antigen-presenting cells of the innate immune system to enhance immunogenicity. immunological diversity an antibody is made up of two