CD8 T cells protect the body against intracellular infections and eliminate cells undergoing uncontrolled growth. Following activation, they rapidly proliferate and acquire the ability to kill target cells. In addition, a subset of CD8 T cells differentiates into memory cells that persist long-term and enable a faster immune response upon re-exposure to the pathogen.
The strength and duration of antigen exposure strongly influence CD8 T-cell function. During chronic infection, T cells receive continuous stimulation through their T-cell receptors (TCRs). Over time, this leads to T-cell exhaustion: cells produce fewer cytotoxic molecules and cytokines, proliferate less efficiently, and upregulate inhibitory receptors. However, they do not become completely inactive and continue to contribute to infection control.
B cells can influence T-cell responses through several mechanisms, including antigen presentation, delivery of costimulatory signals, and regulation of cytokine production. Their role depends on the context of the immune response:
- During acute infection, B cells are not required for CD8 T cell expansion. However, after the active phase of infection resolves, they help maintain memory T cells.
- In autoimmune diseases and following vaccination, B cells are required to sustain CD8 T-cell effector functions.
Until recently, however, it remained unclear under which conditions CD8 T cells depend on B cells.
Scientists from Germany and Australia demonstrated that B cells support CD8 T-cell effector functions during chronic infection. In contrast, during acute infection with lymphocytic choriomeningitis virus (LCMV), B cells had little effect on CD8 T-cell activity.
B cells produced type I interferons (IFN-I), thereby maintaining an inflammatory environment. IFN-I helped exhausted CD8 T cells preserve effector functions under conditions of high antigen burden and strong TCR stimulation. Under weaker TCR stimulation, T cells no longer required this support.
B Cells Are Required for Optimal CD8 T-Cell Responses During Chronic Infection
Experiments in mice showed that the role of B cells depends on the nature of the viral infection:
- During acute LCMV infection, the absence of B cells had only a minor effect on CD8 T-cell responses. Mice retained the ability to generate effector cells and produce the cytokines IFN-γ and TNF.
- During chronic infection, the absence of B cells dramatically reduced the numbers of both exhausted T-cell progenitors (Tpex) and exhausted effector T cells (Tex). By day 5, the number of splenic CD8 T cells had decreased 27-fold, and their ability to produce IFN-γ and TNF was markedly impaired. Viral burden was also increased in B-cell-deficient mice.
The cytokine defect observed during chronic infection was not caused by more severe T-cell exhaustion. The effect was tissue-specific: B cells supported weakened CD8 T-cell responses in the spleen but had little influence on T-cell responses in lymph nodes.
These findings indicate that CD8 T-cell responses during chronic infection depend far more heavily on B cells than responses during acute infection.
B Cells Support CD8 T Cells Independently of CD4 T Cells
The absence of B cells impaired early follicular helper T-cell (Tfh) development and reduced the number of regulatory T cells (Tregs) during both post-acute and chronic LCMV infection. In contrast, T helper 1 (Th1) cell differentiation and NK-cell numbers were largely unaffected. However, during chronic infection, Tfh cells exhibited reduced PD-1 expression, whereas Th1 cells showed lower levels of T-bet and the chemokine receptor CXCR3.
Despite these alterations, changes in CD4 T-cell populations did not account for the effects on CD8 T cells. B cells supported CD8 T-cell proliferation and effector differentiation independently of CD4 T-cell help.
B Cells Promote T-Cell Differentiation in the Spleen but Not in Lymph Nodes
During chronic infection, B cells facilitate the maturation of exhausted CD8 T cells in the spleen. In the absence of B cells, exhausted T-cell progenitors (Tpex) were less likely to differentiate into effector cells.
In lymph nodes, however, B-cell deficiency did not affect CD8 T-cell differentiation. Effector cells in lymph nodes retained greater functional activity, exhibited fewer signs of exhaustion, and were associated with lower viral loads.
Thus, B cells are required for the differentiation of exhausted CD8 T cells in the spleen but are not necessary for the generation of fully functional effector cells in lymph nodes.
The Need for B-Cell Support Depends on Antigen Levels
High antigen burden is a major driver of T-cell exhaustion. The researchers compared CD8 T-cell responses under conditions of high and low antigen load during chronic infection:
- Under high antigen load, the absence of B cells reduced CD8 T-cell proliferation, effector cell formation, and IFN-γ and TNF production.
- Under low antigen load, CD8 T cells maintained strong effector responses even in the absence of B cells and showed fewer signs of exhaustion.
These findings indicate that the strength of TCR stimulation determines the requirement for B-cell support: the higher the antigen burden, the more dependent CD8 T cells become on B cells.
B Cells Prevent the Development of a Tolerant State in CD8 T Cells During Chronic Infection
During chronic infection, CD8 T cells developing in the absence of B cells acquired characteristics of immunological tolerance, a state associated with reduced responsiveness to antigen. These cells showed increased expression of tolerance-associated genes, reduced expression of T-bet—the master regulator of effector differentiation and IFN-γ production—and impaired energy metabolism and mitochondrial function.
Importantly, this state was reversible. After transfer into mice containing B cells, CD8 T cells regained their ability to produce effector cytokines. Conversely, B cell depletion reduced cytokine production even in previously functional T cells.
These findings suggest that during chronic infection, B cells are continuously required to prevent CD8 T cells from entering a tolerant state and to maintain their effector functions and cytokine production.
B Cells Produce IFN-I in Response to Chronic Infection
The absence of B cells did not impair early antigen recognition by CD8 T cells or costimulatory signaling through CD80/CD86. However, splenic IFN-I levels were significantly reduced in B-cell-deficient mice.
Activated B cells directly produced IFN-I during chronic infection. This process did not require antigen recognition via the B-cell receptor but instead depended on TLR7/8 and STING signaling pathways, involving the transcription factors IRF3 and IRF7.
Thus, B cells support CD8 T-cell effector functions by producing IFN-I in response to chronic infection.
IFNAR Blockade Suppresses T-Cell Responses in the Presence of B Cells
Blocking IFN-I signaling in mice with intact B-cell populations impaired the formation of exhausted effector CD8 T cells (Tex) and reduced IFN-γ production. In B-cell-deficient mice, IFN-I blockade produced little additional effect.
The impact depended on antigen load. Under high antigen burden, IFN-I signaling was required for effector T-cell generation, whereas under low antigen burden, blocking IFN-I signaling had only a modest effect.
These results indicate that B cells increase IFN-I availability, thereby supporting CD8 T-cell effector functions at high antigen levels.
IRF1 Supports CD8 T-Cell Expansion Under High Antigen Load
The transcription factor IRF1 was required for vigorous CD8 T-cell proliferation in response to IFN-I. Deletion of IRF1 markedly reduced T-cell expansion, particularly under conditions of high antigen burden and strong TCR stimulation.
When IFN-I signaling was blocked or antigen levels were reduced, the effect of IRF1 deficiency became less pronounced. Notably, IRF1 did not affect Tex formation. Deletion of another regulator, IRF2, caused only a moderate reduction in T-cell responses.
Antigen Load Determines CD8 T-Cell State in Chronic Hepatitis B
Analysis of CD8 T cells from patients with chronic hepatitis B revealed that their functional state depends on the level of viral antigen exposure:
- T cells recognizing the less abundant viral polymerase antigen retained strong effector characteristics.
- In contrast, T cells recognizing the more abundant core antigen showed strong TCR stimulation and immunological tolerance, while acquiring effector functions less efficiently.
Thus, in chronic HBV infection, which does not induce a substantial IFN-I response, low antigen burden allows CD8 T cells to maintain effector activity, whereas high antigen burden impairs effector differentiation.
