DC deficiency syndromes unequivocally demonstrated the nonredundant roles of DCs in mounting the appropriate antimicrobial immune response in infections. Therefore, pathogens have evolved different mechanisms to inhibit DC functions, allowing them to escape from immune recognition and persist in the host. The mechanisms employed by pathogens to inhibit DC functions can be broadly categorized as downregulation of antigen presentation machinery, impairment of microbial sensing, prevention of DC maturation, and induction of immunosuppressive cytokine production. Some examples of how pathogens modulate DC functions are detailed as follows.
Immunodeficiency syndromes can be acquired, which develop later in life through exposure to a causing agent. One example is the acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) infecting CD4+ T cells. As HIV infection occurs through mucosal areas that are rich in DCs, LCs, and imDCs at submucosa encounter and capture the virus early in the infection. HIV encounter may activate imDCs and lead to their migration to LNs, where they can induce antiviral immune responses. pDCs, especially, in response to HIV secrete high levels of type I IFN, which potently inhibits HIV replication. However, HIV can downregulate the expression of co-stimulatory molecules and MHC molecules, which might diminish the efficacy of antiviral T cell induction. DCs may be also susceptible to HIV infection, though much less effectively than CD4+ T cells. The expression of multiple restriction factors in DCs that can block HIV replication renders the productive infection of DCs inefficient.132 However, DCs may still contribute to HIV spread into CD4+ T cells by hosting the virus and enabling its long-term transmission. Additionally, intracellular HIV might be protected from degradation within DCs and may be trafficked to DC-T synapse or released to extracellular milieu by exosomes, thereby mediating HIV transmission to T cells. HIV may also be trapped on the cell surface of follicular DCs and transmitted to T cells through the formation of infectious synapses. DC-SIGN plays a key role in the formation of infectious synapses, in addition to its role as a receptor enabling HIV entry into DCs. Like HIV, both Ebola and Dengue virus also use DC-SIGN to enter DCs.
Human cytomegalovirus (HCMV), also called beta-herpes virus 5, infects the majority of the world population and establishes lifelong infection. Although commonly asymptomatic in healthy individuals, HCMV infection can be fatal in immunocompromised people. HCMV can non-productively infect DCs and modulate DC function. HCMV downregulates MHC class I and II expression in DCs by downregulating ERAP1, inhibiting MHC-II transcription, degrading MHC-II, and interfering with MHC-II and invariant chain interaction. MHC downregulation in DCs enables HCMV escape from T cell recognition. Notably, HCMV can also inhibit NK cell function and avoid NK cell-mediated lysis in absence of MHC-I molecules. HCMV can mediate its inhibitory effects on DCs and T cells also by inducing immunosuppressive cytokine production, such as IL-10. HCMV can encode a functionally active viral IL-10 homolog, as well as induce DCs to produce IL-10.
