ample evidence documents that both cd4 helper and cd8 killer t lymphocytes are critical in the pathogenesis of autoimmune type 1 diabetes ( t1d ) . although the initial events triggering autoreactive responses remain unclear , specific autoantigen presentation by strongly disease - associated major histocompatibility complex ( mhc ) class ii molecules and , according to recent results , weakly disease - associated mhc class i molecules is thought to favor priming and expansion of pathogenic t cells . among the steadily expanding list of autoantigens , many are shared between patients and non - obese diabetic ( nod ) mice , the murine model of the disease . in patients , autoantibodies recognizing four antigens - insulin , glutamic acid decarboxylase ( gad ) , insulinoma antigen-2 , and the recently discovered znt8 - have strong disease - predictive value and are measured in clinical routine diagnostics . other autoantigens such as islet - specific glucose-6-phosphate catalytic subunit - related protein ( igrp ) and the very recently identified chromogranin a   have been studied mainly or exclusively in mice . the critical issue of whether there is one autoantigen whose recognition by t cells is an obligatory triggering event at the onset of the autoimmune response has been much discussed . in the nod model mice tolerized to insulin   or mice expressing exclusively an insulin molecule lacking the immunodominant t - cell epitopes recognized by cd4 and cd8 t cells   develop neither diabetes nor insulitis , whereas similar tolerization to other autoantigens has no such effect . it remains unclear whether insulin or any other antigen plays a similar role in humans . the pivotal role of t cells in t1d has prompted sustained and ongoing efforts to identify autoantigenic epitopes , which can be used to develop t - cell assays potentially useful for disease prediction or monitoring of immunotherapeutic intervention ( or both ) . we   and others   have identified a large number of mainly hla - a2 restricted autoantigenic cd8 t - cell epitopes . using these epitopes , we could develop an enzyme - linked immunosorbent spot ( elispot ) t - cell assay that detected interferon - gamma - secreting t cells in the vast majority of patients at disease onset , whereas recognition seemed to vanish during longer - standing disease . recent studies have identified a number of epitopes derived from the proinsulin signal peptide , whose level of presentation may be proportional to the secretory activity of beta cells . however , a recent blinded study evaluating cd4 t - cell assays found that the sensitivity and specificity of elispot and proliferation assays using purified antigens or epitopes did not exceed 61% and 69% , respectively , a performance greatly inferior to autoantibody assays . moreover , despite much effort spent on t - cell assays , studies showing that t - cell assays are actually useful for predicting or monitoring intervention have not been published as of yet . among the vast number of proteins expressed by beta cells , only a few are prominent targets of the cellular autoimmune response , but the reasons for this selectivity have remained mysterious . one fairly constant but unexplained feature of prominent autoantigens is their association with secretory granules . recent findings provide intriguing new leads with respect to this issue . the bdc2.5 cd4 t - cell clone and t - cell receptor - transgenic mouse line , used in numerous studies , recognize the most recently described autoantigen , chromogranin a , another secretory granule protein . interestingly , the peptide recognized by these cells interacts with only the c - terminal half of the i - ag7 peptide - binding site together with a flanking sequence . this suggests a non - conventional interaction with the t cell in a manner reminiscent of immunodominant cd4 t cells involved in a mouse model of multiple sclerosis . non - conventional peptide - mhc class ii complexes were also shown to play an important role in the recognition of the critical insulin epitope b9 - 23 by pathogenic t cells . mohan and colleagues   found that many islet - infiltrating t cells recognizing this epitope are of  type b ; that is , these cells recognize complexes formed by incubation of antigen - presenting cells with the cognate peptide but not those formed by incubation with the source protein insulin , the latter being recognized only by the molecular mechanism for formation of type b complexes is unclear , but mohan et al . suggest that extremely high antigen concentration , a hallmark of insulin in islets , together with the absence of type b complexes during thymic selection , plays a crucial role in the emergence and stimulation of type b insulin - specific t cells . a specific antigen - processing event could account for the fact that type b complexes may be produced only in islets . the notion that a specific potentially novel antigen - processing pathway may play a role in conferring dominant autoantigen status to insulin is supported by another study . .   showed that the priming of diabetogenic insulin - specific cd8 t cells upon dna vaccination in mice that express the co - stimulatory molecule cd80 in islets depends on translocation of the vaccine - encoded antigen into the endoplasmic reticulum . although the underlying mechanism is entirely unclear , this together with the other cited studies raises the possibility that specific antigen - processing and presentation pathways and events play a role in the autoantigenicity of insulin and possibly other autoantigens . although immunomodulation through cd3-specific antibodies remains the most successful biological therapeutic for t1d , the biological risk necessarily associated with similar strategies has prompted efforts to develop therapeutic strategies based on autoantigens , which are expected to be more specific and safer . in the nod model , it is well established that treatment of prediabetic mice with various autoantigens prevents disease . after a number of unsuccessful trials using insulin in humans , a recent study demonstrated for the first time a beneficial effect of autoantigen administration to patients at disease onset . injection of 20 g of gad in alum resulted in a slower decline of glucose - stimulated c - peptide levels in patients treated no later than 6 months after diagnosis . in these patients ( unlike in anti - cd3-treated patients ) , no reduction in insulin needs was observed , but this result encourages further development of autoantigen - based approaches in humans . a promising novel strategy for the reversal of autoimmunity was very recently described in an elegant study by tsai and colleagues . these authors found that nod mice harbor antigen - experienced cd8 t cells recognizing the highly immunodominant autoantigen igrp , which can be expanded by immunization with nanoparticles coated with specific peptide - mhc complexes . the expanded cells act as suppressors that prevent disease in young mice and , remarkably , reverse disease in overtly diabetic mice , a feat previously unmatched for antigen - based therapies . nanoparticle stimulation of relatively minor t - cell populations also induced the generation of protective suppressor cells , suggesting that the application of the strategy does not require prior identification of immunodominant t - cell populations in every patient treated . among the vast number of proteins expressed by beta cells , only a few are prominent targets of the cellular autoimmune response , but the reasons for this selectivity have remained mysterious . one fairly constant but unexplained feature of prominent autoantigens is their association with secretory granules . recent findings provide intriguing new leads with respect to this issue . the bdc2.5 cd4 t - cell clone and t - cell receptor - transgenic mouse line , used in numerous studies , recognize the most recently described autoantigen , chromogranin a , another secretory granule protein . interestingly , the peptide recognized by these cells interacts with only the c - terminal half of the i - ag7 peptide - binding site together with a flanking sequence . this suggests a non - conventional interaction with the t cell in a manner reminiscent of immunodominant cd4 t cells involved in a mouse model of multiple sclerosis . non - conventional peptide - mhc class ii complexes were also shown to play an important role in the recognition of the critical insulin epitope b9 - 23 by pathogenic t cells . mohan and colleagues   found that many islet - infiltrating t cells recognizing this epitope are of  type b ; that is , these cells recognize complexes formed by incubation of antigen - presenting cells with the cognate peptide but not those formed by incubation with the source protein insulin , the latter being recognized only by the molecular mechanism for formation of type b complexes is unclear , but mohan et al . suggest that extremely high antigen concentration , a hallmark of insulin in islets , together with the absence of type b complexes during thymic selection , plays a crucial role in the emergence and stimulation of type b insulin - specific t cells . a specific antigen - processing event could account for the fact that type b complexes may be produced only in islets . the notion that a specific potentially novel antigen - processing pathway may play a role in conferring dominant autoantigen status to insulin is supported by another study . .   showed that the priming of diabetogenic insulin - specific cd8 t cells upon dna vaccination in mice that express the co - stimulatory molecule cd80 in islets depends on translocation of the vaccine - encoded antigen into the endoplasmic reticulum . although the underlying mechanism is entirely unclear , this together with the other cited studies raises the possibility that specific antigen - processing and presentation pathways and events play a role in the autoantigenicity of insulin and possibly other autoantigens . although immunomodulation through cd3-specific antibodies remains the most successful biological therapeutic for t1d , the biological risk necessarily associated with similar strategies has prompted efforts to develop therapeutic strategies based on autoantigens , which are expected to be more specific and safer . in the nod model , it is well established that treatment of prediabetic mice with various autoantigens prevents disease . after a number of unsuccessful trials using insulin in humans , a recent study demonstrated for the first time a beneficial effect of autoantigen administration to patients at disease onset . injection of 20 g of gad in alum resulted in a slower decline of glucose - stimulated c - peptide levels in patients treated no later than 6 months after diagnosis . in these patients ( unlike in anti - cd3-treated patients ) , no reduction in insulin needs was observed , but this result encourages further development of autoantigen - based approaches in humans . a promising novel strategy for the reversal of autoimmunity was very recently described in an elegant study by tsai and colleagues . these authors found that nod mice harbor antigen - experienced cd8 t cells recognizing the highly immunodominant autoantigen igrp , which can be expanded by immunization with nanoparticles coated with specific peptide - mhc complexes . the expanded cells act as suppressors that prevent disease in young mice and , remarkably , reverse disease in overtly diabetic mice , a feat previously unmatched for antigen - based therapies . nanoparticle stimulation of relatively minor t - cell populations also induced the generation of protective suppressor cells , suggesting that the application of the strategy does not require prior identification of immunodominant t - cell populations in every patient treated . as so often is the case , these intriguing studies leave more questions open than they answer . with respect to the parameters determining autoantigenicity , the general validity of the observed phenomena needs to be studied . is partial filling of the mhc class ii peptide - binding site a common feature of autoantigenic cd4 t - cell epitopes ? can  type b t cells with specificity for autoantigens other than insulin be found ? given that transferred pre - processed epitopes are considered highly unstable and prone to degradation ( at least in the context of mhc class i cross - presentation ) , how does insulin peptide b9 - 23 produced in beta cells ? why does proinsulin targeting to the endoplasmic reticulum increase the priming of pathogenic insulin - specific cd8 t cells ? with regard to therapeutic approaches , the efficacy must be ameliorated greatly if true therapeutic benefits are to be obtained in patients . combination with low - dose immunomodulatory treatments and/or earlier treatment of patients with relatively high c - peptide levels could be roads to follow . t - cell assays with better performance or novel t - cell assays likely will be required before clinical use can be envisaged . finally , t - cell assays should be used to monitor patients at t1d risk and/or patients undergoing immunotherapy to prove the clinical interest of these assays .
recognition of pancreatic beta cell antigens by autoreactive t lymphocytes plays a central role in the pathogenesis of insulin - dependent type 1 diabetes . 
 recent results suggest that non - conventional antigenic epitope processing and presentation may contribute to triggering and maintaining autoreactive responses . 
 moreover , promising results raise hope that autoantigens may become safe and specific therapeutics for type 1 diabetes in the future .