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versial 55 56 clinical significance edit deficiency edit main article t cell deficiency hiv infected t cell causes of t cell deficiency include lymphocytopenia of t cells and or defects on function of individual t cells complete insufficiency of t cell function can result from hereditary conditions such as severe combined immunodeficiency scid omenn syndrome and cartilage hair hypoplasia 57 causes of partial insufficiencies of t cell function include acquired immune deficiency syndrome aids and hereditary conditions such as digeorge syndrome dgs chromosomal breakage syndromes cbss and b cell and t cell combined disorders such as ataxia telangiectasia at and wiskott aldrich syndrome was 57 the main pathogens of concern in t cell deficiencies are intracellular pathogens including herpes simplex virus mycobacterium and listeria 58 also fungal infections are also more common and severe in t cell deficiencies 58 cancer edit further information t cell lymphoma cancer of t cells is termed t cell lymphoma and accounts for perhaps one in ten cases of non hodgkin lymphoma 59 the main forms of t cell lymphoma are extranodal t cell lymphoma cutaneous t cell lymphomas sézary syndrome and mycosis fungoides anaplastic large cell lymphoma angioimmunoblastic t cell lymphoma exhaustion edit t cell exhaustion is a poorly defined or ambiguous term 60 61 there are three approaches to its definition 60 the first approach primarily defines as exhausted the cells that present the same cellular dysfunction typically the absence of an expected effector response the second approach primarily defines as exhausted the cells that are produced by a given cause typically but not necessarily chronic exposure to an antigen finally the third approach primarily defines as exhausted the cells that present the same molecular markers typically programmed cell death protein 1 pd 1 60 indeed it is now starting to emerge that exhaustion might not be the only t cell dysfunctional state 62 in fact tolerization anergy cell death ignorance senesence and exclusion have recently emerged as additional sources and or states of t cell dysfunction in cancer and chronic viral infection 63 dysfunctional t cells are characterized by progressive loss of function changes in transcriptional profiles and sustained expression of inhibitory receptors at first cells lose their ability to produce il 2 and tnfα which is followed by the loss of high proliferative capacity and cytotoxic potential and eventually leads to their deletion exhausted t cells typically indicate higher levels of cd43 cd69 and inhibitory receptors combined with lower expression of cd62l and cd127 exhaustion can develop during chronic infections sepsis and cancer 64 exhausted t cells preserve their functional exhaustion even after repeated antigen exposure 65 during chronic infection and sepsis edit t cell exhaustion can be triggered by several factors like persistent antigen exposure and lack of cd4 t cell help 66 antigen exposure also has effect on the course of exhaustion because longer exposure time and higher viral load increases the severity of t cell exhaustion at least 2 4 weeks exposure is needed to establish exhaustion 67 another factor able to induce exhaustion are inhibitory receptors including programmed cell death protein 1 pd1 ctla 4 t cell membrane protein 3 tim3 and lymphocyte activation gene 3 protein lag3 68 69 soluble molecules such as cytokines il 10 or tgf β are also able to trigger exhaustion 70 71 last known factors that can play a role in t cell exhaustion are regulatory cells t reg cells can be a source of il 10 and tgf β and therefore they can play a role in t cell exhaustion 72 furthermore t cell exhaustion is reverted after depletion of t reg cells and blockade of pd1 73 t cell exhaustion can also occur during sepsis as a result of cytokine storm later after the initial septic encounter anti inflammatory cytokines and pro apoptotic proteins take over to protect the body from damage sepsis also carries high antigen load and inflammation in this stage of sepsis t cell exhaustion increases 74 75 currently there are studies aiming to utilize inhibitory receptor blockades in treatment of sepsis 76 77 78 during transplantation edit while during infection t cell exhaustion can develop following persistent antigen exposure after graft transplant similar situation arises with alloantigen presence 79 it was shown that t cell response diminishes over time after kidney transplant 80 these data suggest t cell exhaustion plays an important role in tolerance of a graft mainly by depletion of alloreactive cd8 t cells 75 81 several studies showed positive effect of chronic infection on graft acceptance and its long term survival mediated partly by t cell exhaustion 82 83 84 it was also shown that recipient t cell exhaustion provides sufficient conditions for nk cell transfer 85 while there are data showing that induction of t cell exhaustion can be beneficial for transplantation it also carries disadvantages among which can be counted increased number of infections and the risk of tumor development 86 during cancer edit see also immunosenescence during cancer t cell exhaustion plays a role in tumor protection according to research some cancer associated cells as well as tumor cells themselves can actively induce t cell exhaustion at the site of tumor 87 88 89 t cell exhaustion can also play a role in cancer relapses as was shown on leukemia 90 some studies have suggested that it is possible to predict relapse of leukemia based on expression of inhibitory receptors pd 1 and tim 3 by t cells 91 many experiments and clinical trials have focused on immune checkpoint blockers in cancer therapy with some of these approved as valid therapies that are now in clinical use 92 inhibitory receptors targeted by those medical procedures are vital in t cell exhaustion and blocking them can reverse these changes 93 see also edit chimeric antigen receptor t 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eoche m lamotte l lion j fumery m marcelo p chatelain d ...