CD8 ⁺ T Cell Exhaustion, Suppressed Gamma Interferon Production, and Delayed Memory Response Induced by Chronic Brucella melitensis Infection

Abstract

dBrucella melitensis is a well-adapted zoonotic pathogen considered a scourge of mankind since recorded history. In some cases, initial infection leads to chronic and reactivating brucellosis, incurring significant morbidity and economic loss. The mechanism by which B. melitensis subverts adaptive immunological memory is poorly understood. Previous work has shown that Brucellaspecific CD8؉ T cells express gamma interferon (IFN-␥) and can transition to long-lived memory cells but are not polyfunctional. In this study, chronic infection of mice with B. melitensis led to CD8 ؉ T cell exhaustion, manifested by programmed cell death 1 (PD-1) and lymphocyte activation gene 3 (LAG-3) expression and a lack of IFN-␥ production. ؉ T cells increased after adoptive transfer in both challenged and unchallenged recipients. CD8 ؉ T cells of challenged recipients initially retained the stunted IFN-␥ production found prior to transfer, and cells from acutely infected mice were never seen to transition to either memory subset at all time points tested, up to 30 days post-primary infection, suggesting a delay in the generation of memory. Here we have identified defects in Brucella-responsive CD8 ؉ T cells that allow chronic persistence of infection. Brucellosis caused by Brucella melitensis has a high incidence in developing countries, and the World Health Organization considers brucellosis one of the seven neglected zoonoses, a group of diseases that contribute to the perpetuation of poverty (1, 2). Brucella has many mechanisms to survive and replicate in hostile host cells, including inducing the unfolded-protein response (UPR), hijacking host nutrients, and counteracting the effects of pH changes, among many others (3-6). The chronic, reactivating nature of Brucella infection, along with its stealthy intracellular life-style, makes infections difficult to clear and requires lengthy antibiotic treatment (7-9). CD8 ϩ T cells control intracellular infections by identifying and killing compromised host cells as a part of the adaptive immune response (10, 11). Recognition of nonself antigenic epitopes in the context of major histocompatibility complex (MHC) class I by cytotoxic T cells also leads to the release of effector molecules to increase local inflammation, thereby "raising the alert" of the host in response to intracellular infection (12). A subset of MHC class I-restricted epitopes of Brucella melitensis generated during infection has been characterized and can elicit specific CD8 ϩ T cells (13). These T cells have been shown to kill their target cells, release cytokines, and survive into the chronic phase of infection (7). Why, then, in the successful establishment of chronic brucellosis, do we see the highly evolved CD8 ϩ T cell arm of adaptive immunity fail to protect the host from long-term infection?Immunological memory is the ability of the host to mount a fast, effective secondary response to infection. CD8 ϩ T cell memory is derived from effectors generated during primary infection or vaccination, a small cohort of ...

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