**2. Differential role of T-regulatory cells and Th-17 cells in malaria**

During malaria, failure in development of an effective pro-inflammatory and anti-inflammatory balance has been found to contribute towards unrestricted replication of parasite and severe immunopathology [31, 33]. Several subsets of T cells (Th-1, Th-2, NKT cells) are involved in controlling the lethal and nonlethal malaria infection [34]. T-reg cells have been primarily found to control the immune evading mechanism of the *Plasmodium* sp. in both mouse and human [35]. A number of other studies have also reported that T-regs may play an important part in facilitating parasite clearance and enhance parasite burden [36, 37]. However, in a separate study, depletion of Foxp3+ T-regs failed to provide protection against experimental cerebral malaria (ECM), which questions the actual role of T-regs in lethal and non-lethal malaria [38]. Augmented generation of Th-17 cells and quick death due to high inflammation in several organs in adult healthy mice upon ablation of T-reg cells, point towards a counter regulatory pathway that might control the pathogenic Th-17 pathway [39]. Th-17 cell itself and cytokines associated with its differentiation from naïve CD4+ T cells has been found to play a role in blood brain barrier (BBB) disruption and cooperate with each other to allow migration of T cells into the brain [40]. As BBB disruption is a salient feature of lethal cerebral malaria, Th-17 pathway and its probable counter regulatory pathway controlled by T-regulatory cells is thought to be important in depicting the probable outcome of the immune response elicited by the host against the malaria parasite. In malaria, the balance between pro-inflammatory and antiinflammatory factors was found to be important when we reported differential expressions of anti-inflammatory TGFβ and pro-inflammatory TNFα and their role in regulation of splenocyte apoptosis [41]. Keeping the outcome of evaluation of TGFβ and TNFα in context to splenocyte apoptosis and shared requirements of TGFβ during differentiation of T-regs and Th-17 cells, we checked whether the balance between anti-inflammatory T regulatory cells and pro-inflammatory Th-17 cells (T-reg/Th-17) is important in malaria immunology in both spleen and brain. T regulatory cells were found to increase in spleen of non-lethal *P. yoelii* infection at 8 days post infection (dpi) in a day specific manner but in case of lethal *P. berghei* ANKA infection, it decreased with an increase in the infection and the percentage of T-regs in spleen was lowest at 8 dpi. Not only Tregs but the transcription factors, specially FOXP3 also showed similar trend in spleen of lethal and non-lethal malaria infection. In contrast to the T-regulatory cells, Th-17 cells increased significantly at 8 dpi in lethal *P. berghei* ANKA infection but decreased optimally at 8 dpi after an initial surge at 2 dpi. The major transcription factor of Th-17 cells shows the similar trend in both lethal and non-lethal malaria infection as does Th-17 cells [42]. Not only in spleen but also in cerebral cortex and cerebellum of the *P. berghei* ANKA infected mice, differential expression of FOXP3 and RORγT has been found to be critical in regulating the glial cell mediated neuroinflammation and neuronal cell death [43]. So, the contrasting behaviour shown

*Regulation of T-reg/Th-17 Balance: One Step Closer Towards Immunotherapy Against Malaria… DOI: http://dx.doi.org/10.5772/intechopen.97045*

by these two cells and their transcription factors highlights the importance of T-reg/Th-17 balance and their regulators in malaria.
