the thymus is a primary lymphoid organ in which bone marrow - derived t - cell precursors undergo differentiation , leading to migration of positively selected thymocytes to the t - cell - dependent areas of secondary lymphoid organs . interactions between thymocytes and specialized thymic microenvironmental cells ( thymic epithelial cells , macrophages , dendritic cells , and fibroblasts ) support and drive t - cell differentiation from bone marrow - derived precursors , by means of a series of interactions including receptor / coreceptor interactions , cytokines , chemokines , and hormones [ 37 ] , as illustrated in figure 1 . thymopoiesis starts at the time that a t - cell precursor enters the thymus and interacts with local microenvironmental cells , which ultimately lead to their proliferation and further differentiation to the t - cell lineage . various types of interactions take place , including those mediated by the class i and class ii major histocompatibility complexes ( mhc ) expressed by microenvironmental cells , extracellular matrix proteins ( ecm ) such as laminin , fibronectin , and collagen , chemokines ( as ccl25 , cxcl12 , ccl21 ) , lectins such as galectin-3 , various typical cytokines ( il-1 , il-2 , il-3 , il-6 , il-7 , il-8 , ifn - gamma , and others ) , sphingosin-1-phosphate ( s1p1 ) , and hormones ( thymulin , thymopoietin , thymosin - a1 ) [ 2 , 5 , 813 ] . t - cell differentiation depends on t - cell receptor ( tcr ) gene rearrangement and membrane interaction with mhc molecules . the mechanisms by which progenitors home to the thymus have been suggested to be similar to those used by leukocytes to enter lymph nodes ( selectins , chemokines receptors , and integrins ) [ 1 , 14 , 15 ] . as soon as these thymic settling progenitors ( tsp ) enter the thymus close to the cortico - medullary junction , they generate early t - cell progenitors ( etp ) or double - negative dn1 thymocytes , known to be cd117/c - kit , cd44 cd25 . etp or dn1 thymocytes evolve to dn2 and dn3 thymocytes that migrate to the subcapsular zone of the thymic lobules , where they rearrange the genes encoding the tcr beta chain , express pre - tcr receptor , and proliferate . at the dn3 stage , the cxcl12/cxcr4 interaction contributes thymocyte proliferation and differentiation towards the dn4 and subsequently cd4cd8 ( dp ) stage [ 1 , 17 ] . maturation progresses with the definite acquisition of tcr , cd4 , and cd8 expression generating dp ; double cells , which constitute 7580% of the whole thymocyte population . thymocytes that do not undergo a productive tcr gene rearrangement die by apoptosis , whereas those expressing productive tcrs interact with peptides presented by molecules of the major histocompatibility complex ( mhc ) , expressed on microenvironmental cells . the result of this interaction determines the fate of thymocytes [ 2 , 9 , 18 ] . the positively selected thymocytes will escape from apoptosis and become mature cd4 or cd8 single - positive ( sp ) t cells ( figure 1 ) . this is a highly rigorous process , and only a small proportion of the double - positive population survives . positive selection also results in lineage commitment so that the lymphocytes can be committed to either the cd4 or cd8 single - positive phenotype , depending on the class of mhc molecule with which the tcr interacts . intrathymic negative selection is essential to establish self - tolerance in the t - cell repertoire , deleting high - avidity tcr signaling thymocytes reacting to self - peptides presented by microenvironmental cells [ 2 , 11 , 18 , 20 ] . interestingly , along with cd4 t - cell differentiation , two distinct groups of cells , with opposite roles , have been reported : the classical cd4 t helper cells ( cells that are able to trigger and/or enhance an immune response in the periphery ) and regulatory cd4cd25foxp3 t cells , which are able to impair a given immune response [ 9 , 21 ] . the data summarized above clearly demonstrate that the thymus is vital for the homeostatic maintenance of peripheral immune system , maturing both effector and regulatory t cells ( figure 1 ) . it has been well documented that the thymus undergoes an age - related atrophy . under normal circumstances , nevertheless , over time , reduced efficacy of the immune system with age increases the rise of opportunistic infections , autoimmunity , and cancer [ 2224 ] . in this paper , we present emerging data regarding accelerated thymus atrophy caused by infected agents and possible impact of this thymic atrophy to the host immune response . moreover , we show that thymic - derived t cells are involved in the dynamics of lymphocyte populations in secondary lymphoid organs during acute trypanosoma cruzi infection . as mentioned above , the thymus senses several exogenous agents , responding with atrophy , promoted by viruses ( hiv , rabies virus ) , parasites ( trypanosoma cruzi , plasmodium berghei , schistosoma mansoni , and trichinella spiralis ) , and fungi ( paracoccidioides brasiliensis and histoplasma capsulatum ) [ 9 , 22 , 2540 ] . the mechanisms involved in the thymic atrophy in infectious disease are not completely elucidated and may vary . nevertheless , common histological features occur , including decrease of cortical thymocytes and loss of clear - cut distinction in the corticomedullary region [ 9 , 38 , 4147 ] . at least in some cases , such atrophy may be transient : biphasic reactions of the thymic cortex , characterized by initial atrophy and further restoration , were reported in experimental infections by histoplasma capsulatum and toxoplasma gondii [ 48 , 49 ] . thymic atrophy in infectious disease may reflect distinct nonmutually excluding events : decreased number of precursor cell entry into the thymus , lower capacity in thymocyte proliferation , increased thymocyte death , and/or increased exit of thymocytes to peripheral lymphoid tissues ( figure 2 ) . although the migratory capacity of t - cell precursors to colonize the thymus in infectious disease remains unknown , data from the literature suggest that parasite - induced thymus atrophy comprises changes in involvement of proliferation , death , and exit of thymocytes . it has been shown that mitogenic responses of thymocytes from t. cruzi acutely infected mice are reduced due to decrease in interleukin ( il)-2 production , which in turn is associated with high levels of il-10 and interferon- . it has also been suggested that changes in thymocyte subset proportions induced by t. spiralis infection are reflected in a reduced capacity of thymocytes to respond to the t - cell mitogen concanavalin a . in contrast , thymocytes from s. mansoni - infected mice apparently exhibit similar concanavalin a - induced proliferative response , as compared to controls . conjointly , these data suggest that some ( but not all ) parasites induce decrease in the ability of thymocytes to proliferate , which in turn account for the resulting thymic atrophy . in the vast majority of infectious diseases coursing with thymic atrophy , the major biological event associated with thymocyte loss is cell death by apoptosis , as seem , for example , in experimental models of trypanosoma cruzi and plasmodium berghei infection . although cd4cd8 thymocytes are the main target population in infection , other subsets as dn and sp cells also depleted in infected thymus [ 30 , 32 , 42 , 63 , 64 ] . glucocorticoid hormones are strong candidates to promote thymic atrophy and thymocyte death in parasitic infections . serum glucocorticoid levels are upregulated in acute infections and promote dp thymocyte apoptosis through caspase-8 and caspase-9 activation [ 9 , 56 , 57 , 65 , 66 ] ( box 1 ) . such rise in serum glucocorticoids has been reported in experimental parasitic diseases such as malaria , american tripanosomiases or chagas disease , african trypanosomiases or sleeping sickness , toxoplasmosis , leishmaniasis , and schistosomiasis [ 51 , 56 , 6772 ] . in experimental acute t. cruzi infection , thymic atrophy and thymocyte depletion have been associated with both tnf and glucocorticoid serum levels [ 44 , 65 , 73 ] . nevertheless , at least in t. t. cruzi - derived transsialidase , as well as host - derived galectin-3 , extracellular atp , and androgens have been pointed out as candidate molecules to enhance thymocyte death [ 44 , 64 , 69 , 7477 ] . conversely , typical cytotoxic molecules such as fas and perforin are not involved in thymus atrophy in t. cruzi infection . t - lymphocyte migration is controlled by several molecular ligand / receptor interactions , including those involving ecm proteins , chemokines , and lectins [ 12 , 13 , 7982 ] . in the thymus of mice acutely infected by t. cruzi or p. berghei alterations in expression of ecm proteins , chemokines , and/or galectin-3 have been described [ 5 , 63 , 64 , 79 , 83 ] , which is in keeping with the abnormal appearance of thymus - derived immature dp lymphocytes in peripheral lymphoid organs and blood from infected hosts . these findings suggest that the premature scape of immature cells from the organ also contributes to the establishment of the thymic atrophy [ 38 , 42 , 84 , 85 ] . accordingly , it has been shown that thymocytes from t. cruzi acutely infected mice exhibited increased migratory responses to fibronectin and that abnormally high numbers of dp t cells migrate from the thymus to peripheral lymphoid organs . studies performed in experimental p. berghei infection have also demonstrated increased expression of ecm proteins , cxcl12 chemokine production , and enhanced migratory response of thymocytes from infected mice , when compared to controls . acute t. cruzi infection in mice leads to strong activation of innate and adaptive immune responses . splenomegaly and expansion in subcutaneous lymph nodes ( scln ) were reported , mediated by persistent t- and b - cell polyclonal activation [ 63 , 8891 ] . conversely , atrophy in thymus and mesenteric lymph nodes ( mln ) has been observed along with infection [ 9 , 43 , 92 ] . we have previously demonstrated that mln atrophy in t. cruzi infection mice was associated with massive lymphocyte apoptosis , mediated by tnf , fas , and caspase-9 [ 63 , 88 , 92 ] . the role of thymus - derived t cells in secondary lymphoid organ dynamics remains unclear . in order to analyze the role of the thymus upon regional immune response in secondary lymphoid organs from acute t. cruzi infected mice , thymectomized male balb / c mice or sham - operated counterparts were infected with 100 blood - derived trypomastigotes from tulahun strain of t. cruzi . in the peak of parasitemia ( 1821  d.p.i ) , mice were killed , and subcutaneous , mesenteric lymph nodes as well as spleen were analyzed . as demonstrated in figure 3 , thymectomy in noninfected mice does not alter lymphocyte counts in the spleen , scln , and mln . however , absence of thymic - derived t cells during acute infection increased the number of splenocytes ( figure 3 ) . in this respect , it has been demonstrated that thymus - derived tcr t cells removed from the spleen exhibit suppressor activity for t lymphocytes . moreover , as showed in thymectomized t. cruzi chronically infected animals , thymic removal may act by downregulating immunoregulatory mechanisms , leading to an exacerbation of autoimmune reactions believed to be involved in the generation of myocardial damage . interestingly , no changes were observed in scln cell expansion and mln atrophy between infected sham and thymectomized mice , suggesting that suppressor t cells migrate preferentially to the spleen ( figure 3 ) . all together , these data indicates that thymic - derived t cells can exert immunoregulatory in the spleen during acute t. cruzi infection . although the precise mechanisms underlying this phenomenon are not completely elucidated , most likely it is linked to a particular pathogen - host relationship . recently , we addressed whether the changes of the thymic microenvironment promoted by an infectious pathogen would also lead to an altered intrathymic negative selection of the t - cell repertoire . by using a t. cruzi acute infection model , we have seen that , despite the alterations observed in the cortex and medullary compartments undergoing a severe atrophy during the acute phase , the changes promoted by the infection in the thymic architecture do not affect the negative selection . although the intrathymic checkpoints necessary to avoid the maturation of t cells expressing potentially autoreactive  forbidden  t - cell receptors are present in the acute phase of murine chagas disease , circulating cd4cd8 t cells have been reported in humans as well as in animals such as mice , chicken , swine , and monkeys [ 9 , 62 , 85 ] . the existence of this unconventional and rare lymphocyte population in the periphery was explained as a premature release of dp cells from the thymus into the periphery , where their maturation into functionally competent single - positive cells continues . most importantly , there is considerable evidence of an increased frequency of peripheral cd4cd8 t cells not only during acute t. cruzi infection but also in viral infections . for example , in human immunodeficiency virus or epstein - barr virus infections , the percentage of dp cells can increase to 20% of all circulating lymphocytes [ 9597 ] . this fluctuation is also present in the secondary lymph nodes as we demonstrated in the experimental model of chagas disease , in which dp - cell subset increases up to 16 times in subcutaneous lymph nodes [ 83 , 85 ] . during the course of infection , these peripheral dp cells acquire an activated phenotype similar to what is described for activated and memory single - positive t cells with high ifn- production , cd44cd69 expression , and cytotoxic activity . furthermore , similar to previous studies showing high cytotoxic activity and effector memory phenotype of extrathymic dp cells in cynomolgus monkeys and in a chimpanzee experimental infection with hepatitis c virus , our results indicate that the dp cells purified from peripheral lymphoid tissues of chagasic animals show cytotoxic activity as compared to nave single - positive cd4 or cd8 t cells . most likely , the presence of peripheral , mature , and activated dp lymphocytes challenges the perception of the t - cell populations involved in adaptive immune responses during the infection . the presence of peripheral activated dp cells with potentially autoreactive tcr may contribute to the immunopathological events possible related to several pathogen infections . in the chagas disease model , we have demonstrated that increased percentages of peripheral blood subset of dp cells exhibiting an activated hla - dr phenotype are associated with severe cardiac forms of human chronic chagas disease . the role of these hla - dr dp t cells in myocardial damage and host pathologies is unknown . however , correlations between the changes in the numbers of dp t - cell subsets and the extent of inflammatory lesions may represent a clinical marker of disease progression in parasitic infections and may help the design of novel therapeutic approaches for controlling infectious diseases .
the thymus is a primary lymphoid organ in which bone marrow - derived t - cell precursors undergo differentiation , leading to migration of positively selected thymocytes to the t - cell - dependent areas of secondary lymphoid organs . 
 this organ can undergo atrophy , caused by several endogenous and exogenous factors such as ageing , hormone fluctuations , and infectious agents . 
 this paper will focus on emerging data on the thymic atrophy caused by infectious agents . 
 we present data on the dynamics of thymus lymphocytes during acute trypanosoma cruzi infection , showing that the resulting thymus atrophy comprises the abnormal release of thymic - derived t cells and may have an impact on host immune response .