Chronic Human Infection with Trypanosoma cruzi Drives CD4+ T Cells to Immune Senescence

Abstract

Previously we found that the frequency of IFN-γ-producing CD8+ T cells specific for Trypanosoma cruzi inversely correlates with disease severity in chronic human Chagas disease along with low levels of IL-2-secreting CD8+ T cells in all clinical stages. This impairment of the parasite-specific T cell responses was associated with phenotypic features of immune senescence of the CD8+ T cell compartment. These data prompted us to address the question of whether the CD4+ T cell compartment also experiences signs of exhaustion. Thus, we performed a functional and phenotypical characterization of T. cruzi-specific and overall CD4+ T cells in chronically infected subjects with different degrees of cardiac dysfunction. The results show an inverse association between disease severity and the frequency of T. cruzi-specific IFN-γ-producing CD4+ T cells. The high expression of CD27 and CD28 with a relative low expression of CD57 found on CD4+IFN-γ + T cells suggests that the effector T cell pool in chronic T. cruzi infection includes a high proportion of newly recruited T cells, but a low frequency of long-term memory cells. The total CD4+ T cell compartment shows signs of senescence and later stages of differentiation associated with more severe stages of the disease. These findings support the hypothesis that long-term T. cruzi infection in humans might exhaust long-lived memory T cells.

The Role of LAT in Increased CD8 + T Cell Exhaustion in Trigeminal Ganglia of Mice Latently Infected with Herpes Simplex Virus 1

“…In line with this, we have previously shown that the level of HSV-1 latency in CD4 Ϫ/Ϫ mice was significantly higher than that in wt mice (48). Also consistent with our results is the finding that expression of Tim-3 and PD-1 on CD4 ϩ T cells can reduce their function (3,16). Recent studies have now demonstrated that in addition to PD-1, upregulation of Tim-3 (T cell immunoglobulin and mucin domain-containing protein 3) is correlated with T cell exhaustion (23,30,33).…”

Trypanosoma cruzi -Induced Activation of Functionally Distinct αβ and γδ CD4 − CD8 − T Cells in Individuals with Polar Forms of Chagas' Disease

“…Studies performed by us and other groups have shown that major T-cell populations, defined by the expression of CD4 and CD8, display phenotypic and functional differences in individuals with different clinical forms of Chagas' disease. To this end, the frequencies of memory cells, as well as senescent cells, have been associated with the chronic cardiac form of Chagas' disease (1,2,23). While these studies have provided critical information, the determination of the contribution of distinct subpopulations to the immunoregulation and functional activities, as well as the antigens that lead to their activation, is critical for the understanding the mechanisms of generation of pathogenic versus protective responses in Chagas' disease.…”

“…It is caused by neuronal and cardiomyocyte damage, ultimately resulting in ventricular dilation and subsequent functional heart failure, which can lead to death (44). Cardiac patients display a T-cell-mediated inflammatory response in situ (13,24,41), which is responsible for the pathology; this inflammatory profile is also observed in circulating activated T cells found at high frequencies in these patients (2,16,19,32). Although it is clear that a plethora of parasite and host factors influences the clinical outcome of Chagas' disease, recent studies have suggested that activation of functionally distinct Tcell populations in T. cruzi-infected individuals may be responsible for the establishment of different clinical forms (17,20).…”

Immunization with Different Viral Antigens Alters the Pattern of T Cell Exhaustion and Latency in Herpes Simplex Virus Type 1-Infected Mice

“…ϩ T cell exhaustion, while currently less widely studied, appears to be no less prevalent, as it has already been implicated in chronic Trypanosoma cruzi, CMV, and HIV infections (1,10,12). More recently, CD4 ϩ Tim-3 ϩ T cells were implicated in primary HSV-1 infection, and by altering the interaction of Tim-3 with its ligand, the authors could produce therapeutic effects on ocular lesions (51,52).…”