Interferon-Gamma From T Follicular Helper Cells Creates Lung-Resident Memory B Cells

During an influenza outbreak, B cells interact with other immune cells before taking alternative courses to defend the body. B cells, which develop into antibody-producing cells, are one route. Another route involves B cells that develop into lung-resident memory B cells, also known as lung-BRMs, which are essential for pulmonary immunity.

Unlike antibody-producing B cells that aid in the battle against the current illness, lung-BRMs move to the lungs from draining lymph nodes. They live there indefinitely and serve as the first line of defense, producing antibodies in the event of an infection.

Understanding the process that produces these lung-BRMs is critical for developing better flu vaccines. According to the World Health Organization, seasonal influenza kills 290,000 to 650,000 people each year. However, flu vaccines are less effective in the elderly, who are the most vulnerable demographic, as compared to younger people. There is also a need for vaccines that are more effective against subsequent forms of a virus.

André Ballesteros-Tato, Ph.D., and colleagues from the University of Alabama at Birmingham have published a mouse-model study in the journal Immunity demonstrating that interferon-gamma produced by T follicular helper cells, or Tfh cells, following intranasal influenza infection is required to initiate the path of B cell differentiation into lung-BRMs. Ballesteros-Tato is an associate professor in the Division of Clinical Immunology and Rheumatology at the University of Alabama in Birmingham.

Tfh and B cells are both present at germinal centers in lymph nodes that drain the lungs during influenza infection. At day 10 of the infection, class-switched memory B lymphocytes primed against the influenza virus begin to develop in the lungs, and their numbers peak at day 30. The UAB researchers discovered, however, that if mice were lacking in Tfh cells or if Tfh cells were blocked by an antibody, lung-BRMs did not accumulate. As a result, Tfh cell assistance is essential for class-switched BRM responses to influenza.

What function do Tfh cells serve?

The UAB researchers discovered that early after infection, preferential differentiation of lung-BRMs coincided with changes in Tfh cell response. They discovered that the number of Tfh cells rapidly grew and peaked between days 10 and 15. By Day 10, early in the flu infection, approximately 40% of Tfh cells were generating interferon-gamma, or INF-; however, its frequency declined precipitously thereafter.

The generation of INF- by Tfh cells was discovered to be critical to the lung-BRM response in flu. Ballesteros-Tato and colleagues discovered that mice with Tfh cells that could not produce INF- had a significantly lower frequency and number of influenza-specific BRMs in their lungs. Furthermore, when mice were later reinfected with a different strain of influenza, the absence of INF-producing Tfh cells, and hence fewer lung-BRMs, was demonstrated to weaken immune protection.

The researchers wondered if the requirement for IFN- signaling in lung-BRM formation was inherent to the responder cells, implying that the interferon was acting within these cells. They discovered that mice with responder cells lacking the INF- receptor had considerably less flu-specific BRMs after influenza virus infection. The transcription factor STAT1 is known to be necessary for efficient INF- signaling within B cells. The researchers discovered that mice with STAT1-deficient B cells did not accumulate flu-specific BRMs after influenza infection.

The researchers discovered that intrinsic IFN–STAT1 signaling promoted expression of the T-bet transcription factor in B cells in the germinal center of lung-draining lymph nodes, and T-bet was required for differentiation into pre-memory B cells that express the surface marker CXCR3. CXCR3+ pre-memory B cells then developed into CXCR3+ memory B cells, which departed the mediastinal lymph nodes and homed to the lung, where they became lung-BRMs.

“In this proposed model, CXCR3+ memory B cells in the mediastinal lymph nodes are the precursors of lung-BRMs,” said Ballesteros-Tato. “Our data provide evidence of a critical role for IFN-γ-producing Tfh cells in generating lung-BRM responses and provide new insights into the mechanisms that fine-tune germinal center B lymphocyte fate decisions after influenza virus infection.”

“This knowledge is essential for designing new vaccine strategies tailored to elicit potent lung-BRM responses, which have the potential to generate enhanced cross-protection to escape variants.”

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