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Dr. Hai Qi’s team reveals a novel mechanism that promotes high-affinity antibody selection

 

Dr. Hai Qi’s team from the School of Medicine at Tsinghua University published a research paper in Nature on April 1, entitled “Affinity-coupled CCL22 promotes positive selection in germinal centres”. This study reveals a new principle that spatiotemporally orchestrate the GC reaction for positive selection.


Affinity-coupled CCL22 promotes positive selection in germinal centres: the help signals of T cells (contact-dependent, affinity coupled) lead B cells to upregulaing CCL22, and CCL22 enables this B cell to recruit more T cells to get more help signals from T cells, and more help signals cause these high affinity cells to express more CCL22 and further recruit T cells. This positive feedback loop promotes high-affinity antibody selection.

Antibodies are an important tool for the immune system to fight virus, bacteria and other pathogens. Vaccines that induce protective antibodies are an critical weapon to curb the spread of multiple pathogens including the SARS-CoV-2. Protective antibodies not only need to specifically recognize the pathogen (antigen), but also bind to the antigen tightly (high affinity) in order to block the infection of cells and tissues by the pathogens. High-affinity antibody secreting cells are mainly differentiated from Germinal Centre (GC) reaction. In GC, B cells with high affinity go through a Darwinian evolutionary screening process and then be selected to become antibody-secreting cells. This process is also called Antibody Affinity Maturation. And in this process, contact-dependent T cell help is a limiting factor for affinity-based selection. Through direct contacts with B cells, T cells transmit these help signals that allow B cells to survive and clonally proliferate. The higher the affinity of B cells, the more help signals they can get, and the easier it is to differentiate into plasma cells. However, due to many reasons, each contact between T cells and B cells in GC dose not maintain long. As a result, even high-affinity B cells need to contact multiple T cells continuously to obtain sufficient help signals to complete the positive selection. There are many B cells and few T cells in GC, and these cells are constantly moving. The probability of effective interactions between high-affinity B cells and T cells directly affects the efficiency of affinity maturation. So, is it totally random for T cells to interact with B cells? They hypothesed that there may be a mechanism that promotes the interactions between T cells and high-affinity B cells, thereby increasing the efficiency of antibody affinity maturation.

The immune system utilizes chemokines to control the directional movement of lymphocytes. So, they speculated that high-affinity B cells might express some chemokines to enhance the ability to recruit T cells. In this study, they found upon receiving the stimulation by the help signals from TFH cells, GC B cells rapidly upregulated CCL22 and to a less extent CCL17. By engaging CCR4 on TFH cells, they adopted two-photon imaging and found CCR4-CCL17/22 mediated chemotaxis promoted TFH cells to more frequently interact with B cells, increasing the chances of the interactions of TFH cells with the chemokine-secreting B cells. Furthermore, by comparing the expression of chemokines in B cells with different affinity and analyzing CCL22-reporter mice, they confirmed that high-affinity B cells in GC expressed more CCL22, and CCL22 could also indicate high-affinity B cells. In vivo, allowing B cells to receive more help signals from T cells in a short period of time can quickly increase the expression of CCL22; if the help signals from T cells are blocked acutely, the expression of CCL22 can be quickly reduced. These results established a chemokine-based intercellular reaction circuit to relate the amount of T-cell help individual B cells recently receive and their subsequent ability to attract more help, as shown in Figure. By construction of different mice models, two important predictions of this positive feedback were proved: one is when all B cells cannot produce chemokines CCL22 and CCL17, the affinity maturation process will slow down; the other is if they are forced to compete with wild-type cells in the same GC, B cells that cannot express CCL22 and CCL17 will suffer from stronger selective pressure due to their lack of ability to recruit T cells to help, and cannot effectively participate in the development of bone-marrow plasma cells. Finally, they also found that human tonsil GC T cells also express chemokine receptor CCR4, GC B cells also upregulate chemokine CCL22 in response to T cell help signals, and those GC B cells that express CCL22 more frequently express the genes that are associated with T cell help signal, suggesting that a similar mechanism is working in human.

This study revealed a new mechanism that promotes the maturation of germinal center antibody affinity in which CCL22 promotes efficient positive selection in the chaotic GC environment through a positive-feedback amplification loop between recent history of T cell help and current ability to attract further help.

Dr. Hai Qi from the School of Medicine at Tsinghua University is the corresponding author of this work. Dr. Bo Liu f is the first author. The work was funded in part by the National Key R&D Program of China, National Natural Science Foundation of China, the Tsinghua-Peking Center for Life Sciences, the Beijing Municipal Science & Technology Commission, and the Beijing Frontier Research Center for Biological Structure.

Links: https://www.nature.com/articles/s41586-021-03239-2