BTLA

Both BTLA and HVEM are expressed on naive T cells. This colocalization on a single cell allows them to interact in a cis manner (on the same cell). This interaction is important in immunological tolerance as shown by the fact that BTLA mouse knockdown is unable to develop tolerance to high doses of ovalbumin.[7] Furthermore, the knockdown also proves that BTLA is dispensable for T cell development as no abnormalities were detected in T cells development.[9]

When a T cell is fully activated HVEM is internalized and this allows BTLA to interact in a trans manner (with molecules on other cells).[9] This enables other cells who express HVEM to regulate activated T cells. Treg cells express HVEM and are able to facilitate immune suppression through interaction with BTLA.[7] Furthermore, the blockage of BTLA together with PD-1 can help reverting the state of exhaustion which further proves the importance of BTLA as an inhibitory molecule.[9] However, in some cases interaction of BTLA and HVEM can have an opposite effect. For instance, in the case of infection with vaccinia virus BTLA and HVEM interaction promotes survival of CD8+ T cells and production of memory cells.[7]

B cell's expression of BTLA is less studied than T cell's but it is clear that peripheral B cells express a high amount of BTLA whereas in bone marrow B cell precursors express a lower amount of BTLA. BTLA has been connected with suppressory function in B cells and its expression is not necessary for B cell development just like in T cells. However, a lower expression of BTLA on B cells in elderly is implied in a less potent response to the influenza vaccine.[7][9]

BTLA can also be found on DCs, with mature DCs having a higher expression of BTLA and immature DCs a lower one. Just like in T cells and B cells, most results show that BTLA and HVEM interaction suppresses the maturation of DCs.[7][9]

In many cases BTLA expression is connected with unfavourable outcomes as it, for instance, inhibits the function of human CD8+ cancer-specific T cells.[10] For example, this is the case of gallbladder cancer where BTLA+ CD8+ T cells are associated with inhibition of anticancer immunity. Similarly, BTLA+ CD8+ T cells show partial dysfunctionality and decrease secretion of IFN-γ in melanoma patients. Therefore, it seems that BTLA can be used as a novel antitumor therapy target. This notion is supported by the fact that in patients with hepatocarcinoma blocking of BTLA signalling increases the secretion of IFN-γ by CD8+ and CD4+ T cells.[9] However, some studies have shown that, for instance, colorectal carcinoma is associated with lower BTLA expression and that the lower BTLA expression is connected with poor survival.[11] Even in some cases of melanoma BTLA+ CD8+ lymphocytes are suggested to be connected with better outcomes of adoptive cell therapy. Hence, it seems that BTLA has rather a context-specific function. This fact should be taken into account if BTLA is to be used as a cancer therapy target.[9]

As in the case of tumors, BTLA seems to be mainly an inhibitory molecule as, for instance, in the case of pulmonary tuberculosis where BTLA expression in CD4+ and CD8+ T cells is connected with the disease progression.[9] Similar results can be seen during helminth infections. When mice are infected by Strongyloides ratti the mice with BTLA knockdown are faster at eliminating the parasite from the intestine probably through the production of IL-9.[12] Furthermore, the course of virus infections seems to be negatively affected by BTLA as well. During chronic hepatitis B infection BTLA impairs T cell response and what's more blocking BTLA leads to T cell proliferation and higher cytokine production. However, as already mentioned in some cases BTLA seems to have a stimulatory role. This is the case of the aforementioned pulmonary tuberculosis where BTLA+ αβ T cells are predominantly of central memory phenotype and fight off Mycobacterium tuberculosis. A further example is an infection with vaccinia virus during which deletion of BTLA or HVEM causes instability and early apoptosis of CD8+ T cells.[9]