Increased TNF-α/IFN-γ/IL-2 and Decreased TNF-α/IFN-γ Production by Central Memory T Cells Are Associated with Protective Responses against Bovine Tuberculosis Following BCG Vaccination

Abstract

Central memory T cell (Tcm) and polyfunctional CD4 T cell responses contribute to vaccine-elicited protection with both human and bovine tuberculosis (TB); however, their combined role in protective immunity to TB is unclear. To address this question, we evaluated polyfunctional cytokine responses by CD4 T cell effector/memory populations from bacille Calmette–Guerin (BCG) vaccinated and non-vaccinated calves by flow cytometry prior to and after aerosol challenge with virulent Mycobacterium bovis. Polyfunctional cytokine expression patterns in the response by Tcm, effector memory, and effector T cell subsets were similar between BCG-vaccinated and M. bovis-infected calves, only differing in magnitude (i.e., infected > vaccinated). BCG vaccination, however, did alter the kinetics of the ensuing response to virulent M. bovis infection. Early after challenge (3 weeks post-infection), non-vaccinates had greater antigen-specific interferon-γ (IFN-γ)/tumor necrosis factor-α (TNF-α) and lesser IFN-γ/TNF-α/IL-2 responses by Tcm cells than did vaccinated animals. Importantly, these differences were also associated with mycobacterial burden upon necropsy. Polyfunctional responses to ESAT-6:CFP10 (antigens not synthesized by BCG strains) were detected in memory subsets, as well as in effector cells, as early as 3 weeks after challenge. These findings suggest that cell fate divergence may occur early after antigen priming in the response to bovine TB and that memory and effector T cells may expand concurrently during the initial phase of the immune response. In summary, robust IFN-γ/TNF-α response by Tcm cells is associated with greater mycobacterial burden, while IFN-γ/TNF-α/IL-2 response by Tcm cells are indicative of a protective response to bovine TB.

Evaluating the Vaccine Potential of a Tetravalent Fusion Protein (rBmHAXT) Vaccine Antigen Against Lymphatic Filariasis in a Mouse Model

“…IFN-γ secreting T CM cells are believed to play a major role in vaccine-induced protection in parasitic infections ( 44 ). Therefore, we measured the percentage of CD62L+ CCR7+ T CM cells that expressed intracellular IFN-γ.…”

Characterization of immune responses of human PBMCs infected with Mycobacterium tuberculosis H37Ra: Impact of donor declared BCG vaccination history on immune responses and M. tuberculosis growth

“…Cattle that were first vaccinated with BCG and then infected with M . bovis had lower level of IFN-γ, TNF-α, and IL-2 than unvaccinated cattle [ 50 ]. However, in our study these changes in Th1 and Th2 cytokines are transient and may not be as effective markers for the assessment of confounding factors as the more stable trends in growth seen with Mtb CFUs.…”

“…Further, it has been demonstrated that BCG vaccinated cattle that were challenged by M . bovis produced expanded effector and central memory T cell populations [ 50 ]. A recent review identified both central and effector memory T cell populations as being key targets of activation in Mtb vaccine studies [ 59 ].…”

BCG revaccination boosts adaptive polyfunctional Th1/Th17 and innate effectors in IGRA+ and IGRA– Indian adults

“…Beyond IFN-γ-and/or IL-2-specific T cell responses, we used the statistically robust COMPASS analysis to probe polyfunctional T cell responses encompassing 8 effectors representing a total of 256 immune subsets (66). Polyfunctional Mtb-specific CD4 + T cells simultaneously expressing IFN-γ, IL-2, and TNF-α in blood are implicated in anti-TB immunity (67,68) and are shown to be critical in modulating vaccine-mediated immunity in murine rechallenge studies (69)(70)(71)(72). Further, we previously showed Mtb-specific polyfunctional cells expressing up to 4 cytokines to be associated with controlled latent infection (49).…”