Researchers at the Hackensack Meridian Centre for Discovery and Innovation (CDI) shared in July 2024 that their paper in Cell Reports presents the identification of an “unconventional” immune response with positive implications for tuberculosis (TB) vaccine development. The authors suggest that, while understanding the role of B cells is “crucial” for TB vaccine development, the changes in B cell immune landscapes during TB remain “incompletely explored”. They used high-dimensional flow cytometry to “map” the immune landscape in response to Mycobacterium tuberculosis (Mtb) infection, concluding that targeting the regulatory function of B cells could be a valuable strategy for TB vaccine development.
TB vaccine challenges
Tuberculosis, caused by infection with Mycobacterium tuberculosis (Mtb), remains a “severe public health threat worldwide”, resulting in 1.6 million deaths a year. A key challenge in controlling the disease is the “lack of reliable vaccines”; the BCG vaccine has “varying efficacy” but the development of an alternative is “hampered by an incomplete understanding of the immune correlates for protection”.
Recent research has “predominantly” addressed T cells in Mtb infection, leaving B cells “not fully understood”. Thus, the authors hope to elucidate their role in immunity and protection and provide “valuable insights” for TB vaccine development. The role of B cells in Mtb infection is unclear, with studies suggesting it ranges from protective to neutral to detrimental.
B cells
B cells can provide a “broad defence spectrum against infections” with heterogeneous subsets displaying “distinct functional characteristics”. These subsets are divided into “conventional and unconventional” B cells based on functional characteristics and immunophenotypes:
- Conventional B cells, also known as follicular B (FoB) cells, represent the “major” B cell subset of around 80% of B cells. They are a “critical component” for adaptive immunity, reacting to infections with “high-affinity antibodies”.
- Unconventional B cells, including marginal one B (MZB) cells, B1 B cells, MZB cell precursors (MZPs), and age-associated B cells (ABCs), are components of innate immunity, responding to infections faster than FoB cells with “low-affinity antibodies”.
B cells “dynamically” change their subset compositions in response to TB, with MZB cell frequency increasing in the blood of active TB patients and the frequency of atypical B cells with ABC phenotype increasing in the blood of both active and latent TB patients.
“Notably, the successful treatment of TB has been found to reverse the alterations in B cell subset compositions. These observations suggest that B cells change their immune landscape in response to the varying status of Mtb infection.”
The study
To “comprehensively” investigate the detailed immune landscape of B cells, the authors used high-dimensional flow cytometry to analyse B cell subsets in infected organs of mouse models. They then depleted the specific B cell subset in mouse models to examine their functional implications on Mtb infection, finding that, in response to infection in the lungs and spleen, B cells “shifted” their immune landscape to favour MZB cells. This contributes to systemic protection by shaping cytokine patterns and cell-mediated immunity.
An important feature of the research is that MZB cells “continuously expanded” throughout Mtb infection, which implies their engagement in both early and chronic phases of TB. MZB cells presented an “activated and memory-like phenotype”, emphasising their “functional distinction” from conventional B cells. The expansion of MZB cells increased the pool of multiple-cytokine-producing B cells to shape systemic cytokine patterns. This means that the accumulation of MZB cells “not only changed the composition B cells throughout the infection but altered the effector functions of B cells”.
Pulmonary and splenic MZB cells exhibited “similar” immunophenotypes and RNA signatures but differed from conventional B cells. Pulmonary MZB cells “might perform functions analogous” to splenic MZB cells. MZB cells are “typically” found in the spleen of healthy mice but have been observed outside the spleen during disease progression or ageing, and the results confirmed the presence of B cells exhibiting the MZB phenotype and RNA signature outside the spleen during infection. However, the origins of the pulmonary MZB cells “remain uncertain”.
As a low frequency of MZB cells was detected in the blood of infected mice, the authors suggest that pulmonary MZB cells were unlikely to have disseminated from the spleen through the bloodstream. Instead, they consider that pulmonary MZB cells could be derived from local FoB cells, with B cell follicles in the infected lungs providing a “suitable environment” for the differentiation. FoB cells have been shown to differentiate into MZPs and then MZB cells with “appropriate stimulation”. Therefore, in response to Mtb infection, pulmonary FoB cells could acquire the MZB phenotype at both protein and RNA levels to “adopt the functions” of splenic MZB cells.
MZB cells during infection
During Mtb infection, MZB cells “displayed a distinct functional profile” in comparison with conventional B cells, exhibiting an “activated and memory-like phenotype”. They expressed higher levels of CD86 and CD80 than conventional B cells, possibly “empowering” them to regulate T and NK cells through interactions with CD28 family receptors. This is a “crucial” mechanism for TB control.
Although MZB cells are usually categorised as innate-like cells, the study suggests that memory-like B cells mainly accumulated in the MZB subset during infection. Additionally, with the “abundant” expression of CD69 on pulmonary MZB cells, they may have served as lung-resident memory B cells, contributing to long-term protection against Mtb infection.
The MZB cells protected against TB through a cytokine pattern that created an anti-TB environment. This is an “unorthodox regulatory function” that differs from conventional B cells. Indeed, the depletion of splenic MZB cells led to an increased Mtb burden and a cytokine pattern that “promoted” TB progression. Polyfunctional CD4 T cells play an “essential role” in controlling TB, and MZB cells reflected these characteristics to produce both TNF- α and IL-2 as well as CXCl1, CCL5, and GM-CSF.
“At the early stage of infection, MZB cells could provide multiple cytokines to serve as an innate defence mechanism, even before the onset of adaptive immunity, like polyfunctional T cells. With the progression of the infection, multiple-cytokine-producing MZB cells continued to expand, maintaining an anti-TB environment throughout the infection.”
Furthermore, MZB cells regulated the dynamics of other cytokine-producing cells through their capacities for multiple cytokine production and co-stimulatory ligand expression. They play a “key role” in executing the regulatory function to provide protection against TB.
“Our results indicate that B cells skew their immune landscape toward MZB cells to execute regulatory functions against TB, emphasising the importance of antibody-independent mechanisms of B cells for controlling infectious diseases, a previously neglected mechanism.”
The researchers hope that the insight they provide will “offer a promising avenue” for TB vaccine development.
“Enhancing MZB cell responses during BCG vaccination may improve vaccine efficacy by using their regulatory functions to shape optimal immune responses. Furthermore, activated and memory-like MZB cells may serve as tissue-resident memory B cells to provide long-term protection.”
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